KR20230005809A - Method for producing monosulfoxide derivatives - Google Patents

Abstract

The present invention provides a method for preparing monosulfoxide.

Description

Method for producing monosulfoxide derivatives

The present invention relates to a method for preparing monosulfoxide derivatives.

Sulfoxide derivatives are attracting attention in fields such as agricultural chemicals (Patent Document 1). Therefore, it is important that sulfoxide derivatives are prepared selectively and in high yield. As a method for producing sulfoxide derivatives, oxidation of sulfide derivatives is known. However, conventional oxidation of sulfide derivatives has the following drawbacks or problems.

Examples 13 and 27 of Patent Document 1 disclose that sulfoxide derivatives can be produced by an oxidation reaction with metachloroperbenzoic acid. However, considering the environmental aspect, the use of metachloroperbenzoic acid is undesirable for industrial production. The reason for this is as follows. After the reaction, metachloroperbenzoic acid becomes waste metachlorobenzoic acid. As a result, the use of metachloroperbenzoic acid places a heavy burden on the environment. In addition, since metachloroperbenzoic acid is expensive, the method using metachloroperbenzoic acid is industrially undesirable.

On the other hand, oxidation using hydrogen peroxide is an industrially preferable and useful method. The reason for this is as follows. Hydrogen peroxide is environmentally friendly because it becomes harmless water after the reaction. And also, hydrogen peroxide is industrially inexpensive.

Patent Literature 2 and Patent Literature 3 disclose that sulfoxide derivatives can be prepared by an oxidation reaction with hydrogen peroxide using a catalyst that essentially requires a ligand. However, ligands are industrially difficult to obtain, and ligands must be prepared in advance. Moreover, it is necessary to prepare a catalyst from a metal compound and a ligand before starting the reaction, and the use of a ligand is industrially undesirable in terms of difficulty and/or cost in industrial production. In addition, a cumbersome operation was required to remove the used ligand. In addition, in the method described in Patent Document 2, a benzoic acid derivative is used. From the above viewpoints, use of benzoic acid derivatives is also industrially undesirable.

Furthermore, for example, in the method described in Patent Literature 2, it has been found that a complicated operation of removing a metal used as a catalyst is also required.

Patent Document 1: International Publication No. 2013/157229 Patent Document 2: International Publication No. 2017/150478 Patent Document 3: US2011/0015405A1 (Japanese Patent No. 2012-532906)

There is an urgent need for a process for preparing sulfoxide derivatives that can address one or more of the drawbacks or problems of the prior art described above.

Accordingly, an object of the present invention is to provide a method for producing a sulfoxide derivative that is industrially desirable, economical, and environmentally friendly. In other words, it has been desired to provide a method that can reduce the environmental load while being inexpensive.

For example, one of the specific objects of the present invention is to prepare a sulfoxide derivative using hydrogen peroxide, which is attracting attention as a clean and excellent oxidizing agent, without using metachloroperbenzoic acid as an oxidizing agent.

Another specific object of the present invention is to provide a simple and inexpensive preparation method that does not use ligands and benzoic acid derivatives. It also avoids the cumbersome task of removing ligands and benzoic acid.

Another specific object of the present invention is to avoid a troublesome operation for removing a metal used as a catalyst.

In addition, in the examination of the oxidation reaction without using a ligand or the like, the following subjects were clarified. The sulfide derivative of the following formula (A) has a structural feature in that it has two sulfide sites that are oxidized in an oxidation reaction. It is necessary to selectively prepare a monosulfoxide derivative while selectively oxidizing only one sulfide site and not oxidizing the other sulfide site.

Details are as follows. In the oxidation reaction of the sulfide derivative of the following formula (A), there is a possibility that a desired compound and an unwanted compound are produced due to two reaction points. The desired product is a monosulfoxide derivative of formula (B), on the other hand a disulfoxide derivative of formula (C) is unnecessary. The disulfoxide derivative of the formula (C), which is an unnecessary by-product, lowers the yield of the desired monosulfoxide derivative of the formula (B). In addition, since the physical properties of both derivatives are similar, in industrial production, by removing the disulfoxide derivative of the formula (C) as a by-product from the crude product after the oxidation reaction, the purified desired monosulfoxide of the formula (B) It is difficult to obtain side derivatives. That is, it is difficult to separate and purify the target product in high yield on an industrial scale. Therefore, it has been desired to be able to selectively produce a monosulfoxide derivative of the desired formula (B) by avoiding non-selective oxidation (i.e., excessive oxidation) to the disulfoxide derivative of the formula (C).

[Formula 1]

In short, another specific object of the present invention is to provide a method capable of producing only a desired monosulfoxide derivative selectively and in high yield from a sulfide derivative having a structural feature of having two sulfide sites to be oxidized. In order to achieve this object, it is necessary to provide a selective oxidation reaction avoiding excessive oxidation.

In view of the above circumstances, the present inventors have intensively studied methods for preparing sulfoxide derivatives. As a result, this inventor unexpectedly discovered that the said subject was solvable by providing the following manufacturing method of the compound of Formula (B). This inventor came to complete this invention based on this knowledge.

That is, the present invention is as follows.

[1] Equation (B):

[Formula 2]

(In the expression,

R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;

R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 halo an alkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; and

n is 5 or 6) as a method for preparing a compound,

Formula (A):

[Formula 3]

(Wherein, R ¹ , R ² , R ³ and n are as defined above) a method comprising an oxidation step of reacting a sulfide derivative with hydrogen peroxide in the presence of a metal catalyst.

[2] R ¹ is a C1-C4 haloalkyl group,

R ² and R ³ are each independently a halogen atom or a C1-C4 alkyl group; and

The method according to [1], wherein n is 5 or 6.

[3] R ¹ is a trifluoromethyl group,

R ² is a fluorine atom and R ³ is a chlorine atom;

or R ² and R ³ are methyl groups; also

The method according to [1], wherein n is 5 or 6.

[4] R ¹ is a trifluoromethyl group,

R ² is a fluorine atom;

R ³ is a chlorine atom; also

The method described in [1], wherein n is 5.

[5] R ¹ is a trifluoromethyl group,

R ² and R ³ are methyl groups; also

The method described in [1], wherein n is 6.

[6] The metal catalyst is at least one (preferably one or two, more preferably one) catalyst selected from the group consisting of a vanadium catalyst, a molybdenum catalyst, and a titanium catalyst,

The method described in any one of [1] to [5].

[7] The metal catalyst is a vanadium catalyst or a molybdenum catalyst,

The method described in any one of [1] to [5].

[8] The metal catalyst is a vanadium catalyst,

The method described in any one of [1] to [5].

[9] The metal catalyst is a molybdenum catalyst,

The method described in any one of [1] to [5].

[10] metal catalyst

Vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium(V) oxide, vanadium oxytrichloride(V),

Titanyl(IV) acetylacetonate, titanium trichloride, titanium tetrachloride, titanium(IV) tetraisopropoxide,

Ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdic acid sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silicomolybdic acid, and sodium silicolybdate

At least one (preferably one or two, more preferably one) catalyst selected from the group consisting of,

The method described in any one of [1] to [5].

[11] The metal catalyst

vanadyl acetylacetonate, vanadium(III) acetylacetonate,

titanyl(IV) acetylacetonate, and

Ammonium molybdate

At least one (preferably one or two, more preferably one) catalyst selected from the group consisting of,

The method described in any one of [1] to [5].

[12] The metal catalyst

Vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium(V) oxide, vanadium oxytrichloride(V),

Ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdic acid sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silicomolybdic acid, and sodium silicolybdate

At least one (preferably one or two, more preferably one) catalyst selected from the group consisting of,

The method described in any one of [1] to [5].

[13] The metal catalyst

vanadyl acetylacetonate, vanadium(III) acetylacetonate, and

Ammonium molybdate

At least one (preferably one or two, more preferably one) catalyst selected from the group consisting of,

The method described in any one of [1] to [5].

[14] The metal catalyst

Vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium(V) oxide, and vanadium oxytrichloride(V)

At least one (preferably one or two, more preferably one) catalyst selected from the group consisting of,

The method described in any one of [1] to [5].

[15] The metal catalyst

Vanadyl acetylacetonate, and vanadium(III) acetylacetonate

At least one (preferably one or two, more preferably one) catalyst selected from the group consisting of

The method described in any one of [1] to [5].

[16] The metal catalyst is vanadyl acetylacetonate,

The method described in any one of [1] to [5].

[17] The metal catalyst

Ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdic acid sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silicomolybdic acid, and sodium silicolybdate

At least one (preferably one or two, more preferably one) catalyst selected from the group consisting of,

The method described in any one of [1] to [5].

[18] The metal catalyst is ammonium molybdate,

The method described in any one of [1] to [5].

[19] The oxidation process is carried out in a solvent,

The method described in [1] to [18].

[20] In the oxidation step, the concentration of the compound of formula (A) at the start of the reaction is 5 to 75% by weight,

The method described in [19].

[21] In the oxidation step, the concentration of the compound of formula (A) at the start of the reaction is 20 to 60% by weight,

The method described in [19].

[22] In the oxidation step, the concentration of the compound of formula (A) at the start of the reaction is 35 to 50% by weight,

The method described in [19].

[23] The solvent is a solvent in which the solubility of the compound of formula (A) is high and the solubility of the compound of formula (B) is low,

The method described in any one of [19] to [22].

[24] The solvent is a solvent in which the solubility of the compound of formula (B) is 55% by weight or less in the range of 15 to 20 ° C.

The method described in any one of [19] to [23].

[25] The solvent is a solvent in which the solubility of the compound of formula (B) is 40% by weight or less in the range of 15 to 20 ° C.

The method described in any one of [19] to [23].

[26] The solvent is a solvent in which the solubility of the compound of formula (B) is 5 to 75% by weight in the range of 15 to 20 ° C.

The method described in any one of [19] to [23].

[27] The solvent is 20 to 55% by weight of the solvent in the range of 15 to 20 ° C. solubility of the compound of formula (B),

The method described in any one of [19] to [23].

[28] The solvent is 30 to 40% by weight of the solvent in the range of 15 to 20 ° C. solubility of the compound of formula (B),

The method described in any one of [19] to [23].

[29] The solvent is a solvent in which the solubility of the compound of formula (A) is 10% by weight or more in the range of 15 to 20 ° C.

The method described in any one of [19] to [28].

[30] The solvent is a solvent in which the solubility of the compound of formula (A) is 30% by weight or more in the range of 15 to 20 ° C.

The method described in any one of [19] to [28].

[31] The solvent is a solvent in which the solubility of the compound of formula (A) is 40% by weight or more in the range of 15 to 20 ° C.

The method described in any one of [19] to [28].

[32] The solvent is a solvent containing alcohol,

The method according to any one of [19] to [31].

[33] The solvent is alcohol or a mixture of alcohol and water (preferably a mixture of alcohol and water),

The method described in any one of [19] to [31].

[34] The alcohol is a C1-C6 aliphatic alcohol (preferably a C1-C5 aliphatic alcohol),

The method described in any one of [32] or [33].

[35] The alcohol is a C1-C4 aliphatic alcohol,

The method described in any one of [32] or [33].

[36] The alcohol is methanol, ethanol, 2-propanol, t-butanol or t-amyl alcohol (preferably methanol, ethanol, 2-propanol or t-butanol),

The method described in any one of [32] or [33].

[37] The alcohol is methanol, 2-propanol, t-butanol or t-amyl alcohol,

The method described in any one of [32] or [33].

[38] The alcohol is 2-propanol, t-butanol or t-amyl alcohol (preferably 2-propanol or t-butanol),

The method described in any one of [32] or [33].

[39] The alcohol is t-butanol or t-amyl alcohol,

The method described in any one of [32] or [33].

[40] the alcohol is t-butanol,

The method described in any one of [32] or [33].

[41] The solvent is a nitrile solvent or an alcohol solvent, or a mixture of a nitrile solvent or an alcohol solvent and water,

The method according to any one of [19] to [31].

[42] The solvent is acetonitrile, methanol, 2-propanol, t-butanol or t-amyl alcohol, or a mixture thereof with water (preferably acetonitrile, 2-propanol, t-butanol or t-amyl alcohol, or a mixture thereof with water) (more preferably acetonitrile, 2-propanol or t-butanol, or a mixture thereof with water) (more preferably a mixture of t-butanol and water, or t-amyl alcohol) a mixture of water) (particularly preferably a mixture of t-butanol and water)

The method described in any one of [19] to [31].

[43] The solvent is acetonitrile or a mixture of acetonitrile and water (preferably a mixture of acetonitrile and water),

The method described in any one of [19] to [31].

[44] The solvent is a halogen-based solvent or a mixture of a halogen-based solvent and water,

The method described in any one of [19] to [31].

[45] The solvent is dichloromethane or a mixture of dichloromethane and water (preferably a mixture of dichloromethane and water),

The method described in any one of [19] to [31].

[46] adding an aqueous hydrogen peroxide solution to a solution containing the compound of Formula (A) and a metal compound,

The method described in any one of [1] to [45].

[47] The oxidation process is performed at -10 ° C to 60 ° C,

The method described in any one of [1] to [46].

[48] The oxidation process is performed at 10 ° C to 35 ° C,

The method described in any one of [1] to [46].

[49] The oxidation process is performed at 25 ° C to 35 ° C,

The method described in any one of [1] to [46].

[50] The oxidation process is performed at 15 ° C to 20 ° C,

The method described in any one of [1] to [46].

[51] The rate at which hydrogen peroxide is added is 0.5 mol/hour or less (preferably 0.1 mol/hour to 0.5 mol/hour) relative to 1 mole of the sulfide derivative of formula (A),

The method described in any one of [1] to [50].

[52] The rate at which hydrogen peroxide is added is 0.05 mol/hour to 0.5 mol/hour with respect to 1 mol of the sulfide derivative of formula (A),

The method described in any one of [1] to [50].

[53] The oxidation step is performed for 3 hours or more (or 6 hours or more),

The method described in any one of [1] to [52].

[54] The oxidation step is performed in 48 hours or less (or 24 hours or less),

The method described in any one of [1] to [53].

[55] In the oxidation step, crystals of the compound of formula (B) are precipitated,

The method described in any one of [1] to [54].

[56] In the oxidation process or after the oxidation process, crystals of the compound of formula (B) are precipitated,

The method described in any one of [1] to [54].

[57] Including a step in which crystals of the compound of formula (B) are precipitated after the oxidation step,

The method described in any one of [1] to [54].

[58] Including a step in which crystals of the compound of formula (B) are precipitated in the oxidation step, or in which crystals of the compound of formula (B) are precipitated after the step,

The method described in any one of [1] to [54].

[59] including a step of recovering crystals of the compound of formula (B) after the oxidation step,

The method described in any one of [1] to [58].

[60] The yield of the compound of formula (B) in the oxidation process is 85 to 100%,

The method described in any one of [1] to [59].

[61] The yield of the compound of formula (B) in the oxidation process is 90 to 100%,

The method described in any one of [1] to [59].

[62] A ligand is not used in the oxidation process,

The method described in any one of [1] to [61].

[63] The ligand is (E)-2-{{(1-hydroxy-2-methylpropan-2-yl)imino}methyl}phenol, and (S)-(2,4-di-tert- The method described in [62], which is butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutan-2-yl)imino]methyl}phenol.

[64] The ligand, formula (D):

[Formula 4]

(Wherein, R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group, a C6-C10 aryl group, a cyano group, a nitro group or a C1-C6 alkoxy group,

R ⁶ is C1-C4 alkyl group, cyano group, nitro group, carboxy group, C1-C4 alkoxycarbonyl group, C1-C4 alkylcarbonyl group, hydroxy C1-C4 alkyl group, C1-C4 alkoxy C1-C4 alkyl group, amino C1-C4 alkyl group; a cyano C1-C4 alkyl group, a nitro C1-C4 alkyl group, a carboxy C1-C4 alkyl group or a C1-C4 alkoxycarbonyl C1-C4 alkyl group;

R ⁷¹ and R ⁷² are each independently a hydrogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group or a C6-C10 aryl group)

The method described in [62], which is a compound of

[65] In the above process, carboxylic acid derivatives are not used,

The method described in any one of [1] to [64].

[66] In the above process, benzoic acid derivatives are not used,

The method described in any one of [1] to [65].

[67] The benzoic acid derivative,

Formula (E):

[Formula 5]

(Wherein, A ¹ , A ² , A ³ , A ⁴ , and A ⁵ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl) amino group, a hydroxy group, or a nitro group. is group;

M is a hydrogen atom, an alkali metal atom or an alkaline earth metal atom;

n is 1 or 2),

The method described in [66].

[68] The benzoic acid derivative is sodium 2,6-dimethoxybenzoate,

The method described in [66].

[69] The amount of hydrogen peroxide used in the oxidation step is 1.0 to 1.5 moles relative to 1 mole of the sulfide derivative of formula (A),

The method described in any one of [1] to [68].

[70] The method according to any one of [1] to [69], wherein the amount of the metal catalyst used in the oxidation step is 0.4 to 3.0 mol% of metal atoms per 1 mole of the sulfide derivative of the formula (A).

[71] Equation (C):

(In the expression,

R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;

R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 halo an alkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

n is 5 or 6)

The method according to any one of [1] to [70], wherein the content of the disulfoxide compound in is 10% or less based on the weight of the compound of the formula (B).

[72] As the method described in [71],

A method in which the content of the disulfoxide derivative of formula (C) is 0% to 10%.

[73] As the method described in [71],

A method in which the content of the disulfoxide derivative of formula (C) is 0% to 5%.

[74] As the method described in [71],

The method in which the content of the disulfoxide derivative of formula (C) is 0% to 2%.

[75] As the method described in [71],

The method in which the content of the disulfoxide derivative of formula (C) is 0% to 1%.

[76] Equation (B):

(In the expression,

R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;

R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 halo an alkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

n is 5 or 6)

As a monosulfoxide derivative of

Formula (C):

(In the expression,

R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;

R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 halo an alkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

n is 5 or 6)

A monosulfoxide derivative wherein the content of the disulfoxide compound in is 10% or less based on the weight of the compound of formula (B).

[77] As the monosulfoxide derivative described in [76],

A monosulfoxide derivative whose content of the disulfoxide derivative of formula (C) is 0% to 10%.

[78] As the monosulfoxide derivative described in [76],

A monosulfoxide derivative whose content of the disulfoxide derivative of formula (C) is 0% to 5%.

[79] As the monosulfoxide derivative described in [76],

A monosulfoxide derivative whose content of the disulfoxide derivative of formula (C) is 0% to 2%.

[80] As the monosulfoxide derivative described in [76],

A monosulfoxide derivative whose content of the disulfoxide derivative of formula (C) is 0% to 1%.

[81] Solid, formula (B):

(Where, R ¹ , R ² , R ³ and n are as defined in [1])

Monosulfoxide derivatives of

[82] Formula (B), which is a crystalline solid:

(Where, R ¹ , R ² , R ³ and n are as defined in [1])

Monosulfoxide derivatives of

[83] Formula (B), solid at 25° C.:

(Where, R ¹ , R ² , R ³ and n are as defined in [1])

Monosulfoxide derivatives of

[84] Formula (B), having a melting point of 40 ° C to 50 ° C:

(Where, R ¹ , R ² , R ³ and n are as defined in [1])

Monosulfoxide derivatives of

[85] Formula (B), having a melting point of 46 ° C to 50 ° C:

(Where, R ¹ , R ² , R ³ and n are as defined in [1])

Monosulfoxide derivatives of

[86] Formula (B), having a melting point of 41 ° C to 45 ° C:

(Where, R ¹ , R ² , R ³ and n are as defined in [1])

Monosulfoxide derivatives of

[87] A monosulfoxide derivative according to any one of [76] to [86],

R ¹ is a C1-C4 haloalkyl group;

R ² and R ³ are each independently a halogen atom or a C1-C4 alkyl group; also

A monosulfoxide derivative wherein n is 5 or 6.

[88] A monosulfoxide derivative according to any one of [76] to [86],

R ¹ is a trifluoromethyl group;

R ² is a fluorine atom and R ³ is a chlorine atom, or R ² and R ³ are a methyl group; also

A monosulfoxide derivative wherein n is 5 or 6.

[89] A monosulfoxide derivative according to any one of [76] to [86],

R ¹ is a trifluoromethyl group;

R ² is a fluorine atom;

R ³ is a chlorine atom; also

A monosulfoxide derivative wherein n is 5.

[90] A monosulfoxide derivative according to any one of [76] to [86],

R ¹ is a trifluoromethyl group;

R ² and R ³ are methyl groups; also

A monosulfoxide derivative wherein n is 6.

[91]

The method according to any one of [1] to [90], wherein the compound of formula (B) is a crystal.

[92]

Formula (B):

(In the expression,

R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;

R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalky a nyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

n is 5 or 6)

As a compound of

Formula (C):

(In the expression,

R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;

R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalky a nyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

n is 5 or 6)

A compound of formula (B) wherein the content of the compound of is 10% or less based on the weight of the compound of formula (B).

[93]

The powder X-ray diffraction spectrum shows diffraction angles 2θ = 8.9°±0.2°, 10.3°±0.2°, 13.6°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 20.5°±0.2°, 21.8°±0.2° Equation ( Determination of the compound of B-a).

According to the present invention, a novel and industrially applicable production method of the monosulfoxide derivative of the formula (B) useful as an acaricide or the like is provided. According to the present invention, there is provided a method for preparing a sulfoxide derivative capable of solving one or more of the above-mentioned drawbacks or problems in the prior art. Therefore, it is possible to provide a method capable of reducing the environmental load while being inexpensive.

For example, a sulfoxide derivative can be prepared using hydrogen peroxide, which is attracting attention as a clean and excellent oxidizing agent, without using metachloroperbenzoic acid as an oxidizing agent.

In addition, a simple and inexpensive production method that does not use a ligand or a benzoic acid derivative can be provided. Accordingly, cumbersome work for removing ligands and benzoic acid derivatives can be avoided.

Moreover, troublesome operation for removing the metal used as a catalyst can be avoided.

In addition, it is possible to provide a method capable of producing only a desired monosulfoxide derivative selectively and in high yield from a sulfide derivative having a structural feature of having two sulfide sites to be oxidized. That is, it is possible to provide a selective oxidation reaction avoiding excessive oxidation.

Therefore, the method of the present invention is industrially desirable, economical and environmentally friendly.

[Figure 1]
It is a powder X-ray diffraction spectrum of the crystal of the compound of formula (Ba) obtained in Example 20. White crystals of the compound of formula (Ba) were obtained by the same production method as in Example 16. Here, a crystal obtained in the same manner as in Example 16 was used as a seed crystal. The obtained crystals were vacuum dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction analysis. Powder X-ray diffraction measurement results are shown in FIG. 1 .
[Figure 2]
It is a powder X-ray diffraction spectrum of the crystal of the compound of formula (Ba) obtained in Example 21. White crystals of the compound of formula (Ba) were obtained by the same production method as in Example 16. Here, crystals obtained in the same manner as in Example 16 were used as seed crystals. The obtained crystals were melted, dried under reduced pressure to remove moisture, and then cooled. The obtained crystals were pulverized with a mill. The melting point was 47°C to 48°C. The obtained crystals were subjected to powder X-ray diffraction analysis. Powder X-ray diffraction measurement results are shown in FIG. 2 .
[Figure 3]
It is a powder X-ray diffraction spectrum of the crystal of the compound of formula (Ba) obtained in Example 22. White crystals of the compound of formula (Ba) were obtained by the same production method as in Example 1. Recrystallization was performed on the obtained crystal. Here, the recrystallization conditions are the same as the crystallization conditions of Example 1 (recrystallization from 2-propanol and water). The obtained crystals were filtered and dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction analysis. Powder X-ray diffraction measurement results are shown in FIG. 3 .

Hereinafter, the present invention will be described in detail.

The method according to the present invention comprises the following oxidation process:

[Formula 6]

(In the formula, R ¹ , R ² , R ³ and n are as described in [1] above)

represented by

Terms and symbols used in this specification are described below.

A halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. From the viewpoints of usefulness and economy of the product, etc., preferable examples of the halogen atom are a fluorine atom and a chlorine atom.

Examples of alkali metal atoms include lithium atoms, sodium atoms, potassium atoms, rubidium atoms and cesium atoms, preferably lithium atoms, sodium atoms, potassium atoms and cesium atoms, more preferably lithium atoms, sodium atoms and potassium atoms. do.

Examples of the alkaline earth metal atom include a magnesium atom, a calcium atom, a strontium atom and a barium atom, preferably a magnesium atom, a calcium atom and a barium atom.

"Ca-Cb" means that the number of carbon atoms is a to b. For example, "C1-C4" in "C1-C4 alkyl group" means that the number of carbon atoms in the alkyl group is 1 to 4.

In this specification, a general term such as "alkyl" is interpreted to include both straight and branched chains such as butyl and tert-butyl. On the other hand, for example, the specific term "butyl" means straight-chain "normal butyl" and does not mean branched-chain "tert-butyl". And branched chain isomers such as "tert-butyl" are specifically mentioned when intended. As another example, the specific term "propyl" means straight-chain "normal propyl" and does not mean branched-chain "isopropyl". And branched chain isomers such as "isopropyl" are specifically mentioned when intended.

In this specification, the following abbreviations and prefixes may be used, and their meanings are as follows.

Me: methyl

Et: ethyl

Pr, n-Pr and Pr-n: profile (i.e. normal profile)

i-Pr and Pr-i: isopropyl

Bu, n-Bu and Bu-n: butyl (i.e. normal butyl)

s-Bu and Bu-s: sec-butyl (ie secondary butyl)

i-Bu and Bu-i: isobutyl

t-Bu and Bu-t: tert-butyl (i.e., tert-butyl)

Ph: Phenyl

n-: normal

s- and sec-: secondary

i- and iso-: iso

t- and tert-: Tertory

c- and cyc-: cyclo

o-: ortho

m-: meta

p-: para

A C1-C6 alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms.

Examples of the C1-C6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group,

butyl group, sec-butyl group, isobutyl group, tert-butyl group,

A pentyl group, a hexyl group, etc. are included, but are not limited to these.

A C1-C4 alkyl group means a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms.

Examples of C1-C4 alkyl groups are suitable examples among the above examples of C1-C4 alkyl groups.

A C2-C4 alkenyl group means a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms. Examples of the C2-C4 alkenyl group include a vinyl group (i.e. ethenyl group), 1-propenyl group, 2-propenyl group, isopropenyl group (i.e. 1-methylvinyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 1,3-butadienyl group, and the like, but are not limited thereto.

A C2-C4 alkynyl group means a straight-chain or branched-chain alkynyl group having 2 to 4 carbon atoms. Examples of the C2-C4 alkynyl group include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, etc., but these is not limited to

A haloalkyl group means a straight-chain or branched-chain alkyl group substituted with one or more identical or different halogen atoms.

A C1-C4 haloalkyl group means a straight-chain or branched chain alkyl group having 1 to 4 carbon atoms substituted with 1 to 9 identical or different halogen atoms (here, the halogen atom has the same meaning as defined above). ).

Examples of C1-C4 haloalkyl groups include:

A fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorodifluoromethyl group,

2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group,

3-fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 2,2,3,3,3-pentafluoropropyl group, 2,2,2-trifluoro-1-trifluoro Romethylethyl group, heptafluoropropyl group, 1,2,2,2-tetrafluoro-1-trifluoromethylethyl group,

4-fluorobutyl group, 4-chlorobutyl group, 4-bromobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, etc., but are not limited thereto. .

A C2-C4 haloalkenyl group means a straight or branched chain alkenyl group having 2 to 4 carbon atoms substituted with 1 to 7 identical or different halogen atoms (here, the halogen atom has the same meaning as defined above). have). Examples of the C2-C4 haloalkenyl group include 1-fluorovinyl group, 1-chlorovinyl group, 2-fluorovinyl group, 2-chlorovinyl group, 2,2-difluorovinyl group, and trifluorovinyl group. , 2-fluoro-2-propenyl group, 2-chloro-2-propenyl group, 3-fluoro-2-propenyl group, 3-chloro-2-propenyl group, 3,3-difluoro-2-pro Phenyl group, 3,3-dichloro-2-propenyl group, 2,3-difluoro-2-propenyl group, 2,3-dichloro-2-propenyl group, 2,3,3-trifluoro-2-pro Phenyl group, 1-(chloromethyl)vinyl group, 1-(trifluoromethyl)vinyl group, 1-trifluoromethyl-2,2-difluorovinyl group, 4,4-difluoro-3-butene yl group, 3,4,4-trifluoro-3-butenyl group and the like, but are not limited thereto.

A C2-C4 haloalkynyl group means a straight-chain or branched-chain alkynyl group having 2 to 4 carbon atoms and substituted with 1 to 5 identical or different halogen atoms (where the halogen atom is as defined above). Examples of the C2-C4 haloalkynyl group include 2-fluoroethynyl group, 2-chloroethynyl group, 3-fluoro-1-propynyl group, 3-chloro-1-propynyl group, 1- Fluoro-2-propynyl group, 1-chloro-2-propynyl group, 3-fluoro-2-propynyl group, 3-chloro-2-propynyl group, 1,1-difluoro-2-propynyl group, 4 -Fluoro-3-butynyl group, 4-chloro-3-butynyl group, 4,4-difluoro-2-butynyl group, 4,4,4-trifluoro-2-butynyl group, etc. It is not limited to these.

The C1-C4 alkoxy group means a (C1-C4 alkyl)-O- group (here, the C1-C4 alkyl group portion has the same meaning as defined above).

Examples of C1-C4 alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, butoxy groups, sec-butoxy groups, isobutoxy groups, tert-butoxy groups, and the like not.

The C1-C4 haloalkoxy group means a (C1-C4 haloalkyl)-O- group (here, the C1-C4 haloalkyl group portion has the same meaning as above).

Examples of C1-C4 haloalkoxy groups are

A fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a chlorodifluoromethoxy group,

2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group period,

3-fluoropropoxyl group, 3-chloropropoxyl group, 3-bromopropoxyl group, 2,2,3,3,3-pentafluoropropoxyl group, 2,2,2-trifluoro- 1-trifluoromethylethoxy group, heptafluoropropoxy group, 1,2,2,2-tetrafluoro-1-trifluoromethylethoxy group,

4-fluorobutoxy group, 4-chlorobutoxy group, 4-bromobutoxy group, 2,2,3,3,4,4,4-heptafluorobutoxy group, and the like, but are not limited to these not.

The phenyl C1-C6 alkyl group means a C1-C6 alkyl group substituted by a phenyl group (here, the C1-C6 alkyl group portion has the same meaning as defined above).

Examples of the phenylC1-C6 alkyl group include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 5-phenylpentyl group, a 6-phenylhexyl group, and the like, but these is not limited to

The C6-C10 aryl group means an aromatic cyclic group in which all atoms constituting the ring are 6 to 10 carbon atoms.

Examples of the C6-C10 aryl group are a phenyl group, a 1-naphthyl group and a 2-naphthyl group. A 1-naphthyl group is also referred to as a naphthalen-1-yl group. A 2-naphthyl group is also called a naphthalen-2-yl group.

A C1-C4 alkoxycarbonyl group means a (C1-C4 alkyl)-O-C(=O)- group (here, the C1-C4 alkyl group portion has the same meaning as defined above).

Examples of the C1-C4 alkoxycarbonyl group include, but are not limited to, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and the like.

A C1-C4 alkylcarbonyl group means a (C1-C4 alkyl)-C(=O)- group (here, the C1-C4 alkyl group portion has the same meaning as defined above).

Examples of the C1-C4 alkylcarbonyl group include, but are not limited to, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, and the like.

A hydroxy C1-C4 alkyl group means a C1-C4 alkyl group substituted by a hydroxy group (here, the C1-C4 alkyl group has the same meaning as above).

Examples of the hydroxyC1-C4 alkyl group are hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 1-hydroxybutyl group, 2-hydroxy butyl group, 3-hydroxybutyl group and the like, but are not limited thereto.

The C1-C4 alkoxyC1-C4 alkyl group means a C1-C4 alkyl group substituted by a C1-C4 alkoxy group (here, the C1-C4 alkoxy group and C1-C4 alkyl group have the same meaning as above).

Examples of C1-C4 alkoxyC1-C4 alkyl groups include:

A methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, an isopropoxymethyl group,

1-methoxyethyl group, 2-methoxyethyl group, 1-ethoxyethyl group, 2-ethoxyethyl group, 1-propoxyethyl group, 2-propoxyethyl group, 1-isopropoxyethyl group, 2-isopropoxyethyl group,

1-methoxypropyl group, 2-methoxypropyl group, 3-methoxypropyl group,

1-methoxybutyl group, 2-methoxybutyl group, 3-methoxybutyl group, 4-methoxybutyl group and the like, but are not limited thereto.

An amino C1-C4 alkyl group means a C1-C4 alkyl group substituted by an amino group (here, the C1-C4 alkyl group has the same meaning as above).

Examples of the amino C1-C4 alkyl group are aminomethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-aminopropyl group, 2-aminopropyl group, 1-aminobutyl group, 2-aminobutyl group, 3-aminobutyl group and the like, but are not limited thereto.

The cyano C1-C4 alkyl group means a C1-C4 alkyl group substituted by a cyano group (here, the C1-C4 alkyl group has the same meaning as above).

Examples of the cyano C1-C4 alkyl group include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl, 1-cyanobutyl, 2-cyano butyl group, 3-cyanobutyl group and the like, but are not limited thereto.

The nitroC1-C4alkyl group means a C1-C4alkyl group substituted by a nitro group (here, the C1-C4alkyl group has the same meaning as above).

Examples of the nitroC1-C4 alkyl group are nitromethyl group, 1-nitroethyl group, 2-nitroethyl group, 1-nitropropyl group, 2-nitropropyl group, 1-nitrobutyl group, 2-nitrobutyl group, 3-nitrobutyl group and the like, but are not limited thereto.

A carboxy C1-C4 alkyl group means a C1-C4 alkyl group substituted by a carboxy group (here, the C1-C4 alkyl group has the same meaning as above).

Examples of the carboxyC1-C4alkyl group are carboxymethyl group, 1-carboxyethyl group, 2-carboxyethyl group, 1-carboxypropyl group, 2-carboxypropyl group, 1-carboxybutyl group, 2-carboxybutyl group, 3-carboxybutyl group and the like, but are not limited thereto.

The C1-C4 alkoxycarbonyl C1-C4 alkyl group means a C1-C4 alkyl group substituted by a C1-C4 alkoxycarbonyl group (here, the C1-C4 alkoxycarbonyl group and the C1-C4 alkyl group have the same meaning as above).

Examples of C1-C4 alkoxycarbonylC1-C4 alkyl groups include:

methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, isopropoxycarbonylmethyl group,

1-methoxycarbonylethyl group, 2-methoxycarbonylethyl group, 1-ethoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 1-propoxycarbonylethyl group, 2-propoxycarbonylethyl group, 1- isopropoxycarbonylethyl group, 2-isopropoxycarbonylethyl group,

1-methoxycarbonylpropyl group, 2-methoxycarbonylpropyl group, 3-methoxycarbonylpropyl group,

1-methoxycarbonylbutyl group, 2-methoxycarbonylbutyl group, 3-methoxycarbonylbutyl group, 4-methoxycarbonylbutyl group and the like, but are not limited thereto.

The (C1-C4 alkyl)amino group means a (C1-C4 alkyl)-NH- group (here, the C1-C4 alkyl group part has the same meaning as defined above).

Examples of the (C1-C4 alkyl)amino group include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, and the like.

Definitions and examples of functional groups other than the above can be understood by those skilled in the art as well as the above functional groups.

In the present specification, a compound having isomers includes all isomers and any mixture thereof in an arbitrary ratio. For example, xylene includes o-xylene, m-xylene, p-xylene and any mixtures thereof in any proportion. For example, dichlorobenzene includes o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene and any mixtures thereof in any proportion.

In this specification, the non-limiting term "comprise(s)/comprising" may be arbitrarily replaced with the limited phrase "consist(s) of/consisting of".

In this specification, the term “recover/recover” may be arbitrarily replaced with “separate/separate”. In the present specification, the sulfide derivative of formula (A) is synonymous with the compound of formula (A), the monosulfoxide derivative of (B) is synonymous with the compound of (B), and the disulfoxide derivative of formula (C) is synonymous with the compound of formula (C).

Unless indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

Unless otherwise indicated, numbers representing characteristics such as amounts, sizes, concentrations, reaction conditions, etc., used herein are understood to be modified by the term "about." In some embodiments, the disclosed numbers are interpreted using the number of reported significant digits and applying conventional rounding techniques. In some embodiments, the disclosed numbers are to be interpreted as including errors necessarily resulting from the standard deviation found in their respective testing measurements.

(Raw compound: sulfide derivative of formula (A))

Preparation of the sulfide derivative of the formula (A) is described in, for example, International Publication No. 2013/157229 (Patent Document 1), or may be performed by a similar method.

[Formula 7]

Specific examples of the sulfide derivative of formula (A) The preparation of the compound of (A-a) is as shown in the figure below.

[Formula 8]

From the point of view of usefulness and economy of the product, etc., a preferred combination of R ¹ , R ² , R ³ and n in formula (A) is:

R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;

R ² and R ³ are each independently a halogen atom or a C1-C4 alkyl group; also

n is 5 or 6;

In view of the above, a more preferred combination of R ¹ , R ² , R ³ and n in formula (A) is:

R ¹ is a C1-C4 haloalkyl group;

R ² and R ³ are each independently a halogen atom or a C1-C4 alkyl group; also

n is 5 or 6;

In view of the above, a more preferred combination of R ¹ , R ² , R ³ and n in formula (A) is:

R ¹ is a trifluoromethyl group;

R ² is a fluorine atom;

R ³ is a chlorine atom, or

R ² and R ³ are methyl groups; also

n is 5 or 6;

In one aspect, in view of the above, a more preferred specific combination of R ¹ , R ² , R ³ and n in formula (A) is:

R ¹ is a trifluoromethyl group;

R ² is a fluorine atom;

R ³ is a chlorine atom; also

n is 5.

In another aspect, in view of the above, a more preferred specific combination of R ¹ , R ² , R ³ and n in formula (A) is:

R ¹ is a trifluoromethyl group;

R ² and R ³ are methyl groups; also

n is 6.

In view of the foregoing, particularly preferred specific combinations of R ¹ , R ² , R ³ and n in formula (A) are:

R ¹ is a trifluoromethyl group;

R ² is a fluorine atom;

R ³ is a chlorine atom; also

n is 5.

(Object compound: monosulfoxide derivative of formula (B))

In view of the above, preferred combinations, more specific combinations, further preferred combinations, and particularly preferred combinations of R ¹ , R ² , R ³ and n in formula (B) are the same as those in formula (A) described above. .

Particularly preferred specific examples of compounds of formula (B) are the compounds of formula (B-a) below.

[Formula 9]

As described above, in the method for producing the monosulfoxide derivative of formula (B) from the compound of formula (A), the oxidation reaction proceeds sufficiently and the ratio of the disulfoxide derivative of formula (C) in the product is sufficiently high. Low is desired. The content of the compound of formula (C) in the reaction mixture after the oxidation reaction is, for example, 10% or less (0% to 10%), preferably 0% to 7%, based on the weight of the compound of formula (B). It may be more preferably 0% to 5%, more preferably 0% to 3%, still more preferably 0% to 2%, and particularly preferably 0% to 1%.

(oxidizing agent; hydrogen peroxide)

The oxidizing agent used in the present invention may be any oxidizing agent as long as the reaction proceeds. An oxidizing agent capable of oxidizing a corresponding raw material compound (sulfide derivative) to a target compound (monosulfoxide derivative) can be used. Examples of the oxidizing agent used in the present invention include, but are not limited to, inorganic peroxides (eg, hydrogen peroxide, urea-hydrogen peroxide adducts, etc.) and the like. From the viewpoints of safety, reactivity, selectivity and economic efficiency, etc., a preferred oxidizing agent is hydrogen peroxide. You may use an oxidizing agent individually or in combination of 2 or more types in arbitrary ratios.

An oxidizing agent is used in the present invention. The form of the oxidizing agent may be any form as long as the reaction proceeds. The type of oxidizing agent can be appropriately selected by a person skilled in the art. When using hydrogen peroxide as an oxidizing agent, the form of hydrogen peroxide may be any form as long as the reaction proceeds. Considering safety, risk, economic efficiency, etc., examples of preferred forms of hydrogen peroxide are 5 to 60 wt% aqueous hydrogen peroxide solution, preferably 5 to 40 wt% hydrogen peroxide aqueous solution, more preferably 10 to 35 wt% hydrogen peroxide aqueous solution, and further preferably a 25 to 35 wt% hydrogen peroxide aqueous solution. In addition, in this specification, "30% hydrogen peroxide aqueous solution" is also called "30% hydrogen peroxide", for example.

(Amount of oxidizing agent)

The amount of the oxidizing agent (preferably hydrogen peroxide) used in the method of the present invention may be any amount as long as the reaction proceeds.

From the viewpoint of yield improvement and economic efficiency, etc., the lower limit of the amount of the oxidizing agent (preferably hydrogen peroxide) used in the present invention is, for example, 0.9 per mole of the sulfide derivative (raw material compound) of the formula (A). mol or more, preferably 1.0 mol or more.

From the viewpoints of safety, suppression of by-products and economic efficiency, the upper limit of the amount of the oxidizing agent (preferably hydrogen peroxide) used in the present invention is, for example, 1 mole of the sulfide derivative (raw compound) of the formula (A) , may be 2.0 moles or less, preferably 1.7 moles or less, and more preferably 1.5 moles or less.

In addition, the usage-amount of the oxidizing agent (preferably hydrogen peroxide) in this invention can be suitable and arbitrary combination of the said lower limit and upper limit. Therefore, from the viewpoints of safety, improvement of yield, suppression of by-products, and economic efficiency, the amount of oxidizing agent (preferably hydrogen peroxide) used in the present invention is, for example, the sulfide derivative of formula (A) (raw material 0.9 to 2.0 moles, preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.7 moles, still more preferably 1.0 to 1.5 moles, and particularly preferably 1.0 to 1.2 moles, per mole of compound). However, the usage amount of the oxidizing agent (preferably hydrogen peroxide) in the present invention can be appropriately adjusted by a person skilled in the art depending on the purpose and situation.

(metal catalyst)

The metal catalyst in this invention is demonstrated. The metal catalyst used in the present invention may be any metal catalyst as long as the reaction proceeds. The metal catalyst used in the present invention is a known compound or a compound that can be prepared from a known compound according to a known method.

Metal catalysts include, but are not limited to, metal acetylacetonates, metal oxyacetylacetonates, metal halides, metal oxyhalides, metal oxides, and metal alkoxides.

The metal of the metal catalyst is preferably a transition metal.

Examples of metal catalysts include, but are not limited to, iron catalysts, vanadium catalysts, titanium catalysts, manganese catalysts, copper catalysts, molybdenum catalysts, zirconium catalysts, tungsten catalysts, niobium catalysts, tantalum catalysts, thallium catalysts, and the like.

From the viewpoint of yield, by-product suppression, economic efficiency, etc., the metal catalyst is preferably one or more (preferably one or two, more preferably 1 type), more preferably a vanadium catalyst or a molybdenum catalyst, more preferably a vanadium catalyst.

Examples of iron catalysts are iron(III) acetylacetonate, iron(III) chloride, iron(III) bromide, iron(III) methoxide, iron(III) ethoxide, iron(III) propoxide, iron(III) but is not limited to isopropoxide, iron(III) nitrate, and the like, and mixtures thereof. "Iron(III) acetylacetonate" is also referred to as "Fe(acac) ₃ " or "tris(2,4-pentanedionato)iron(III)".

In the method described in WO2017/150478 (Patent Document 2), the reaction mixture became dirty black due to the iron catalyst used. Further, several times of washing with dilute sulfuric acid was required to remove the iron catalyst.

Examples of vanadium catalysts are vanadyl acetylacetonate, vanadium (III) acetylacetonate, vanadium (V) oxytrichloride, vanadium (V) oxide, vanadium (V) oxytriethoxide, triisopropoxy vanadium (V) oxide, etc., and mixtures thereof, but are not limited thereto. "Vanadyl acetylacetonate" is also referred to as "VO(acac) ₂ ", "bis(2,4-pentanedionato)vanadium(IV) oxide" or "vanadium(IV) oxyacetylacetonate". "Triisopropoxyvanadium (V) oxide" is also referred to as "VO(OiPr) ₃ " or "triisopropoxyoxovanadium (V)". In view of the above, preferable examples of the vanadium catalyst include vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium(V)oxytrichloride and vanadium(V)oxide. More preferred examples of the vanadium catalyst include vanadyl acetylacetonate, vanadium(III) acetylacetonate and vanadium(V) oxide. More preferred examples of vanadium catalysts include vanadyl acetylacetonate and vanadium(III) acetylacetonate. A particularly preferred example of a vanadium catalyst is vanadyl acetylacetonate.

Examples of titanium catalysts are titanium tetrachloride, titanium trichloride, titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, titanium(IV) tert-butoxide , titanyl(IV) acetylacetonate, and the like, and mixtures thereof. "Titanyl(IV) acetylacetonate" is also referred to as "TiO(acac) ₂ ", "bis(2,4-pentanedionato)titanium(IV) oxide" or "titanium(IV) oxyacetylacetonate" . In view of the above, preferred examples of the titanium catalyst include titanium tetrachloride, titanium trichloride, titanium(IV) tetraisopropoxide and titanyl(IV) acetylacetonate. More preferred examples of titanium catalysts include titanium tetrachloride, titanium trichloride and titanyl(IV) acetylacetonate. A particularly preferred example of titanium is titanyl(IV) acetylacetonate.

Examples of manganese catalysts include, but are not limited to, potassium permanganate, manganese(III) acetylacetonate, manganese(II) chloride, manganese(II) oxide, and the like, and mixtures thereof. "Manganese (III) acetylacetonate" is also referred to as "Mn(acac) ₃ ".

Examples of copper catalysts include copper (II) acetylacetonate, copper (I) chloride, copper (II) chloride, copper (I) acetate, copper (II) acetate, copper (I) bromide, copper (I) iodide, etc. and including, but not limited to, mixtures thereof. "Copper (II) acetylacetonate" is also referred to as "Cu(acac) ₂ ".

Examples of molybdenum catalysts include molybdenyl acetylacetonate, molybdic acid, sodium molybdate (including sodium molybdate dihydrate), potassium molybdate, ammonium molybdate (including ammonium molybdate tetrahydrate), molybdenum oxide ( For example, molybdenum oxide (VI)), molybdenum chloride (eg, molybdenum chloride (V)), molybdenum sulfide (eg, molybdenum sulfide (IV)), phosphomolybdic acid, sodium phosphomolybdate, molybdenum phosphomolybdenum ammonium acid, silicomolybdic acid, sodium silicomolybdate, and the like, and mixtures thereof, but are not limited thereto. "Molybdenyl acetylacetonate" is also referred to as "MoO ₂ (acac) ₂ ", "bis (2,4-pentanedionato) molybdenum (VI) dioxide" or "molybdenum (IV) deoxyacetylacetonate" . In view of the above, preferred examples of the molybdenum catalyst are ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdenum sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, and silicon molybdenum. acids and sodium silicolybdate. More preferable examples of the molybdenum catalyst include ammonium molybdate, sodium molybdate, potassium molybdate and molybdenum oxide. More preferred examples of the molybdenum catalyst include ammonium molybdate, sodium molybdate and potassium molybdate. A particularly preferred example of the molybdenum catalyst is ammonium molybdate (eg, ammonium molybdate tetrahydrate).

Among molybdenum compounds, ammonium molybdate is a catalyst used for Trost oxidation. Trost oxidation is commonly used for oxidation of sulfide compounds to sulfone compounds, as also described in Journal of the American Chemical Society 2009, 131, 47, 17087-17089. However, unexpectedly, in this reaction, the reaction is completed with the monosulfoxide compound, and excessive oxidation to the compound of the formula (C) can also be suppressed.

Examples of zirconium catalysts include zirconium(IV) acetylacetonate, zirconium tetrachloride, zirconium oxychloride (eg zirconium(IV) oxychloride octahydrate (ZrCl ₂ O 8H ₂ O) including) and the like, but is not limited thereto. "Zirconium(IV) acetylacetonate" is also referred to as "Zr(acac) ₄ " or "tetrakis(2,4-pentanedionato)zirconium(IV)".

Examples of tungsten catalysts include tungstate acid, sodium tungstate (including sodium tungstate dihydrate and sodium tungstate decahydrate), potassium tungstate, calcium tungstate, and ammonium tungstate (including ammonium paratungstate pentahydrate). , tungsten (VI) oxide (also called tungsten trioxide), tungsten chloride (VI) (also called tungsten hexachloride), tungsten (V) bromide, tungsten (IV) sulfide (also called tungsten disulfide), tungsten phosphonic acid, tungsten phosphon sodium tungstate, ammonium phosphate tungstate, silicotungstate, sodium silicotungstate, and the like, and mixtures thereof, but are not limited thereto.

Examples of niobium catalysts include, but are not limited to, niobium carbide, niobium (V) chloride, niobium (V) pentaethoxide, and the like, and mixtures thereof.

Examples of tantalum catalysts include, but are not limited to, tantalum carbide (TaC), tantalum (V) chloride (TaCl ₅ ), tantalum (V) pentaethoxide (Ta(OEt) ₅ ), and the like, and mixtures thereof. .

Examples of thallium catalysts include, but are not limited to, thallium(III) nitrate, thallium(III) acetate, thallium(III) trifluoroacetate, and the like, and mixtures thereof.

You may use the metal compound in this invention individually or in combination of 2 or more types of arbitrary ratios. The form of the metal catalyst in the present invention may be any form as long as the reaction proceeds. The shape of the metal catalyst in the present invention can be appropriately selected by those skilled in the art.

(Usage of metal catalyst)

The usage amount of the metal catalyst in the method of the present invention may be any amount as long as the reaction proceeds. In one aspect, from the viewpoints of yield improvement, reduction of environmental load, and economic efficiency, the amount of metal catalyst used in the present invention is, for example, sulfide derivative (raw material compound) of formula (A) 1 0.1 to 20.0 mol%, preferably 0.1 to 10.0 mol%, more preferably 0.1 to 5.0 mol%, still more preferably 0.1 to 3.0 mol%, more preferably 0.1 to 2.0 mol%, relative to moles Preferably it may be 0.1 to 1.0 mol%. In another aspect, from the above viewpoint, for example, the amount of the metal compound used in the present invention is preferably, as a metal atom, per 1 mol of the sulfide derivative (raw compound) of the formula (A). is 0.3 to 6.0 mol%, more preferably 0.3 to 5.0 mol%, still more preferably 0.4 to 5.0 mol%, even more preferably 0.4 to 4.0 mol%, still more preferably 0.4 to 3.0 mol%, particularly preferably may be 0.5 to 2.0 mol%. However, the usage amount of the metal catalyst in the present invention can be appropriately adjusted by a person skilled in the art depending on the purpose and situation.

(ligand)

A ligand that does not need to be used in the present invention will be described. Even without using a ligand, the reaction of the present invention proceeds sufficiently. Therefore, from the viewpoint of economic efficiency and the like, the ligand is preferably not used in the present invention.

Examples of ligands not used in the present invention are formula (D):

[Formula 10]

(In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷¹ and R ⁷² are as follows)

Including, but not limited to, compounds of

In formula (D), R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a phenylC1-C6 alkyl group, a C6-C10 aryl group, a cyano group, a nitro group or a C1-C6 alkoxy group. .

In formula (D), R ⁶ is a C1-C4 alkyl group, a cyano group, a nitro group, a carboxy group, a C1-C4 alkoxycarbonyl group, a C1-C4 alkylcarbonyl group, a hydroxyC1-C4 alkyl group, a C1-C4 alkoxyC1-C4 alkyl group, Amino C1-C4 alkyl group, cyano C1-C4 alkyl group, nitro C1-C4 alkyl group, carboxy C1-C4 alkyl group or C1-C4 alkoxycarbonyl C1-C4 alkyl group.

In formula (D), R ⁷¹ and R ⁷² are each independently a hydrogen atom, a C1-C6 alkyl group, a phenylC1-C6 alkyl group or a C6-C10 aryl group.

Specific examples of ligands not used in the present invention are shown below.

2,4-di-t-butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutane-2-, for example, described in WO2011/006646 (Patent Document 3) 1) imino] methyl} phenol, and the compounds (3-1) to (3-13) described in WO2017/150478 (Patent Document 2), that is,

(E)-2-{[(1-hydroxy-3-methylbutan-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxybutan-2-yl)imino] no]methyl}phenol, (E)-2-{[(1-hydroxypropan-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxy-2-methylpropane -2-yl)imino]methyl}phenol, (E)-2-{[(2-hydroxyethyl)imino]methyl}phenol, (E)-2-{[(1-hydroxy-2- Methylpropan-2-yl)imino]methyl}-4-methylphenol, (E)-2-{[(1-hydroxy-2-methylpropan-2-yl)imino]methyl}-4-methyl Toxyphenol, (E)-4-fluoro-2-{[(1-hydroxy-2-methylpropan-2-yl)imino]methyl}phenol, (E)-4-chloro-2-{[ (1-hydroxy-2-methylpropan-2-yl)imino]methyl}phenol, (E)-4-bromo-2-{[(1-hydroxy-2-methylpropan-2-yl) imino]methyl}phenol, (E)-2-{[(1-hydroxy-2-methylpropane)-2-yl)imino]methyl}-4-iodophenol, (E)-2-{ [(2-hydroxy-1-phenylethyl)imino]methyl}phenol, (E)-4-chloro-2-{[(1-hydroxy-3-methylbutan-2-yl)imino]methyl }phenol, (E)-4-chloro-2-{[(2-hydroxyethyl)imino]methyl}phenol,

Compounds 1a to 1d described in Chemical European Journal, 2005, 11, 1086-1092, J. Legros et al, namely,

(E)-2-{[(1-hydroxy-3,3-dimethylbutanon-2-yl)imino]methyl}-4,6-diiodophenol, (E)-2-{[( 1-hydroxy-3,3-dimethylbutanon-2-yl)imino]methyl}-4,6-dibromophenol, (E)-2-{[(1-hydroxy-3,3- Dimethylbutanon-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxy-3-methylbutan-2-yl)imino]methyl}-4,6-diio Although dophenol etc., it is not limited to these.

(benzoic acid derivative)

Benzoic acid derivatives that do not need to be used in the present invention will be described. The reaction of the present invention proceeds sufficiently even without using a carboxylic acid derivative such as a benzoic acid derivative. Therefore, from the viewpoint of economic efficiency and the like, in the present invention, carboxylic acid derivatives such as benzoic acid derivatives are preferably not used.

Examples of benzoic acid derivatives not used in the present invention are formula (E):

[Formula 11]

(In the formula, A ¹ , A ² , A ³ , A ⁴ , A ⁵ , M and n are as follows)

Including, but not limited to, compounds of

In formula (E),

A ¹ is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxy group or a nitro group;

A ² is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxy group or a nitro group;

A ³ is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxy group or a nitro group;

A ⁴ is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxy group or a nitro group;

A ₅ is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxy group or a nitro group.

In formula (E), M is a hydrogen atom, an alkali metal atom, or an alkaline earth metal atom.

Specific examples of M include, but are not limited to, a hydrogen atom, a lithium atom, a sodium atom, a potassium atom, a cesium atom, a magnesium atom, a calcium atom, and a barium atom.

In formula (E), n is 1 or 2. More specifically, as long as it is chemically acceptable, n may be 1 or 2. For example, when M is a hydrogen atom or an alkali metal atom, n is 1. As another example, n is 2 when M is an alkaline earth metal atom.

Specific examples of carboxylic acid derivatives such as benzoic acid derivatives not used in the present invention are shown below.

For example, benzoic acid derivatives of (4-1) to (4-19) described in WO2017/150478 (Patent Document 2), namely, 2,6-dimethoxysodium benzoate and 2,4,6-trimethine Sodium Toxybenzoate, Sodium 2,4-Dimethoxybenzoate, Sodium 3,4,5-Trimethoxybenzoate, Sodium 4-Methoxybenzoate, Sodium 4-Dimethylaminobenzoate, Sodium 2,6-Dihydroxybenzoate, 4 -Sodium hydroxybenzoate, sodium 4-aminobenzoate, sodium 2,4,6-trimethylbenzoate, sodium 4-t-butylbenzoate, sodium benzoate, lithium 2,6-dimethoxybenzoate, potassium 2,6-dimethoxybenzoate , cesium 2,6-dimethoxybenzoate, magnesium 2,6-dimethoxybenzoate, calcium 2,6-dimethoxybenzoate, barium 2,6-dimethoxybenzoate, sodium 2-methoxybenzoate,

Chemical European Journal, 2005, 11, 1086-1092, AH1 to AH18 and carboxylic acid derivatives (including benzoic acid derivatives) of ANa7, ALi7, AK7, ACs7, ABu ₄ N7 described in J. Legros et al. Not limited.

(Method for producing sulfoxide derivatives)

A monosulfoxide derivative of formula (B) can be produced by adding an oxidizing agent dropwise to a solution containing the sulfide derivative of formula (A) and a metal catalyst. However, as long as the reaction proceeds, the order of adding raw materials, reagents, solvents and the like can be appropriately selected and adjusted by those skilled in the art.

(menstruum)

The solvent in the reaction of the present invention may be any solvent as long as the reaction proceeds. However, from the viewpoint of smooth progress of the reaction, etc., the reaction of the present invention is preferably carried out in the presence of a solvent. In addition, the solubility of the compound of formula (A) is high. Also preferred is a solvent in which the compound of formula (B) has low solubility. In other words, a solvent in which the solubility of the compound of formula (A) is higher than the solubility of the compound of formula (B) is preferred.

As the kind of solvent in the reaction of the present invention, for example,

water,

Halogenated aliphatic hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane, trichloroethane, trichloroethylene, tetrachloroethane, tetrachloroethane, chloroethylene, pentachloroethane, etc., preferably dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, more preferably dichloromethane)

Aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, chlorotoluene, benzotrifluoride, 4-chlorobenzotrifluoride, difluorobenzene, bromethane mobenzene, nitrobenzene, etc., preferably toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene),

nitriles (eg, acetonitrile, propionitrile, butyronitrile, etc., preferably acetonitrile);

carboxylic acid esters (eg, ethyl acetate, isopropyl acetate, butyl acetate, etc.);

Amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP), etc., preferably Preferably N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), more preferably N,N-dimethylformamide (DMF)),

Alkyl ureas (eg, N,N'-dimethylimidazolidinone (DMI), etc.),

sulfones (eg, sulfolane, etc.);

Carbonic acid esters (e.g., ethylene carbonate, propylene carbonate, etc.)

Alcohols (e.g., methanol, ethanol, propanol (i.e. 1-propanol), 2-propanol, n-butanol, s-butanol, i-butanol, t-butanol, pentanol (i.e. 1-pentanol) , s-amyl alcohol, isoamyl alcohol, t-amyl alcohol, hexanol (i.e., 1-hexanol), cyclohexanol, C1-C6 aliphatic alcohols such as ethylene glycol, preferably methanol, ethanol, propanol, C1-C5 aliphatic alcohols such as 2-propanol, n-butanol, s-butanol, i-butanol, t-butanol, pentanol, s-amyl alcohol, isoamyl alcohol, t-amyl alcohol and ethylene glycol, more preferred C1-C4 aliphatic alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, s-butanol, i-butanol, t-butanol, ethylene glycol),

Ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl Methyl ether (CPME), methyl-tert-butyl ether (MTBE), tert-amylmethyl ether (TAME), 1,2-dimethoxyethane (DME), diglyme, triglyme, 4- methoxybenzene, diphenyl ether, etc.), and

including, but not limited to, any combination of them in any ratio.

However, it is preferable to contain alcohol in one aspect. In another aspect, it is preferable to include nitriles. In another aspect, it is preferable to include alcohols or/and nitriles. These are the following "preferred examples of the solvent", "more preferable examples of the solvent", "more preferable examples of the solvent", "preferred examples of the solvent", "more preferable examples of the solvent", and "more preferable examples of the solvent". Yes” can be applied to any of them.

“2-propanol” is also referred to as “isopropyl alcohol” or “isopropanol”.

"t-butanol" is also referred to as "tert-butanol" or "tert-butyl alcohol".

From the viewpoint of reactivity and economic efficiency, etc., preferable examples of the solvent are water, halogenated aliphatic hydrocarbons, aromatic hydrocarbon derivatives, nitriles, carboxylic acid esters, amides, alcohols, and any combination thereof in any ratio. includes

More preferable examples of the solvent include water, nitriles, amides, alcohols and any combination thereof in any ratio.

More preferable examples of the solvent include water, nitriles, alcohols and any combination thereof in any ratio.

Particularly preferred examples of the solvent include water, alcohols and any combination thereof in any proportion.

Preferred specific examples of the solvent are water, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, acetonitrile, ethyl acetate, isopropyl acetate, butyl acetate, N,N -Dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), methanol, ethanol, propanol, 2-propanol, butanol, t-butanol, t-amyl alcohol, and any combination thereof in any ratio.

More preferred specific examples of the solvent are water, acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, propanol, 2-propanol, butanol, t-butanol, t-amyl alcohol, and any ratio any combination thereof.

More preferred embodiments of the solvent include water, acetonitrile, methanol, ethanol, propanol, 2-propanol, butanol, t-butanol, t-amyl alcohol, and any combination thereof in any ratio.

In one aspect, a more preferred embodiment of the solvent includes water, 2-propanol, t-butanol, and any combination thereof in any proportion.

In another aspect, a more preferred embodiment of the solvent includes water, t-butanol, t-amyl alcohol, and any combination thereof in any proportion. Among them, a t-butanol solvent, a t-amyl alcohol solvent, a mixed solvent of t-butanol and water, or a mixed solvent of t-amyl alcohol and water is more preferable. In the present invention, from the viewpoint of safety, it has been found that among alcohols, tertiary alcohols such as t-butanol and t-amyl alcohol are preferable as solvents. From the viewpoint of price, economic efficiency, etc., a t-butanol solvent or a mixed solvent of t-butanol and water is more preferable. From the ease of handling, it was found that a mixed solvent of t-butanol and water is more preferable.

In another aspect, from the above viewpoint, a mixed solvent of t-butanol and water or a mixed solvent of t-amyl alcohol and water is preferred, and a mixed solvent of t-butanol and water is particularly preferred.

The amount of solvent used may be any amount as long as the reaction proceeds. From the viewpoints of yield improvement, suppression of by-products, and economic efficiency, etc., the amount of the solvent used is, for example, 0.01 to 10.0 L (liter), relative to 1 mol of the sulfide derivative (raw compound) of the formula (A), preferably 0.1 to 5.0 L, more preferably 0.3 to 2.0 L, even more preferably 0.4 to 1.5 L, still more preferably 0.4 to 1.2 L, still more preferably 0.5 to 1.2 L, still more preferably 0.5 to 1.5 L It may be 1.0 L. However, the amount of solvent used in the reaction of the present invention can be appropriately adjusted by those skilled in the art. When using a combination of two or more solvents, the ratio of the two or more solvents may be any ratio as long as the reaction proceeds.

However, from the viewpoints of yield, by-product suppression, economic efficiency, etc., in one aspect, the amount of the water solvent in the total solvent consisting of solvents other than water and the water solvent is, for example, the amount of the total solvent (100 vol%) 0 vol% to 100 vol%, preferably 0 vol% to 30 vol%, more preferably 0 vol% to 20 vol%, still more preferably 0 vol% to 15 vol%. In another aspect, the amount of the water solvent in the total solvent consisting of solvents other than water and the water solvent is, for example, 5 vol% to 100 vol%, preferably 5 vol%, relative to the total amount of solvent (100 vol%) to 30 vol%, more preferably 5 vol% to 20 vol%, still more preferably 5 vol% to 15 vol%.

Examples of solvents other than water include alcohols (eg, methanol, 2-propanol, t-butanol, t-amyl alcohol) and nitriles (eg, acetonitrile), but are not limited thereto.

(solubility)

From the standpoint of simple operation, etc., the solubility of the compound in the solvent is preferably a solubility in which the target compound, Formula (B), precipitates without dissolving, but is not limited thereto.

As the solubility of the compound in the reaction solvent of the present invention, for example, the solubility of the target compound of the formula (B) in the range of 15 ° C to 20 ° C is preferably 5 to 75% by weight, more preferably 10 to 75% by weight. 60% by weight, more preferably 20 to 55% by weight, particularly preferably 30 to 40% by weight.

In addition, it is preferable that the compound of formula (A) as a raw material is dissolved in a solvent from the viewpoint of smooth progress of the reaction. The solubility of the compound of formula (A) as a raw material in the range of 15°C to 20°C is, for example, preferably 5 to 75% by weight, more preferably 10 to 55% by weight, particularly preferably 30 to 40% by weight. may be %.

In one embodiment, the solubility of the compound of formula (B-a) in eg 2-propanol was found to be 30 to 40% by weight in the range of 15°C to 20°C. In another embodiment, from the viewpoint of crystallization and filtration, the solubility of the compound of formula (B-a) in a 70% by weight t-butanol/water mixed solution is 4 to 6% by weight in the range of 15 ° C to 20 ° C, and also 5 ° C It was found to be about 2% by weight.

(density)

From the viewpoint of smooth progress of the reaction and simple operation, etc., the concentration of the compound of formula (A) at the start of the reaction is, for example, 5 to 75% by weight, more preferably 20 to 60% by weight, particularly preferably 35 to 50% by weight. The concentration of the compound of formula (A) is the concentration with respect to the entire reaction system.

(reaction temperature)

The reaction temperature of the present invention is not particularly limited. In one aspect, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency, the reaction temperature is, for example,

-10°C to 60°C (i.e. minus 10°C to plus 60°C);

preferably 0°C to 60°C (i.e. zero°C to plus 60°C);

more preferably 5°C to 40°C (i.e., plus 5°C to plus 40°C);

more preferably 10°C to 35°C (i.e., plus 10°C to plus 35°C);

More preferably, it may range from 10°C to 20°C (ie, plus 10°C to plus 20°C). In another aspect, from the above viewpoint, the reaction temperature is, for example,

-20°C to 50°C (i.e. minus 20°C to plus 50°C);

preferably -10°C to 40°C (i.e. minus 10°C to plus 40°C);

More preferably -5 ° C to 35 ° C (ie, minus 5 ° C to plus 35 ° C),

more preferably 15°C to 35°C (i.e. plus 15°C to plus 30°C);

More preferably, it may be in the range of 25°C to 35°C (ie, plus 25°C to plus 35°C). In another aspect, from the above viewpoint, the reaction temperature is, for example,

-10°C to 60°C (i.e. minus 10°C to plus 60°C);

preferably -10°C to 50°C (i.e. minus 10°C to plus 50°C);

More preferably 0 ° C to 50 ° C (ie, zero ° C to 50 ° C),

More preferably, it may be in the range of 0°C to 40°C (ie, zero°C to 40°C).

(reaction time)

The reaction time of the present invention is not particularly limited. The lower limit of the reaction time may be, for example, 2 hours or more, preferably 3 hours or more, and more preferably 6 hours or more, but is not limited thereto. The upper limit of the reaction time may be, for example, 48 hours or less, preferably 24 hours or less, and more preferably 12 hours or less, but is not limited thereto. The range of reaction time in this invention can be suitably adjusted by those skilled in the art by combining said upper limit and lower limit. The combination of the upper and lower limits of the reaction time may be, for example, 2 hours to 48 hours, preferably 2 hours to 24 hours, and more preferably 3 hours to 12 hours, but is not limited thereto. However, the reaction time of the present invention can be appropriately adjusted by a person skilled in the art.

"Reaction time" means the time from when addition of hydrogen peroxide is started to when reaction is complete|finished. The reaction time in the present invention is an aging period for consuming unreacted raw materials. In the present invention, the reaction time is preferably equal to the addition time of hydrogen peroxide, but the present invention is not limited thereto. In the present invention, raw materials are consumed immediately after hydrogen peroxide is added, and hydrogen peroxide does not accumulate in the reaction mixture. Therefore, the present invention is a safe and industrial manufacturing method.

(addition rate of hydrogen peroxide)

It is preferable that the addition rate of hydrogen peroxide is 0.5 mol/hour or less with respect to 1 mol of the compound of Formula (A). When the addition rate is 0.5 mol/hour or less, hydrogen peroxide does not accumulate in the reaction mixture. The upper limit of the addition rate may be, for example, 0.5 mol/hour or less, 0.4 mol/hour or less, and 0.3 mol/hour or less.

Incidentally, from the viewpoints of by-product suppression and economic efficiency, etc., the lower limit of the addition rate may be, for example, 0.05 mol/hour or more, 0.1 mol/hour or more, and 0.2 mol/hour or more.

The range of the addition rate in the present invention can be appropriately adjusted by those skilled in the art by combining the above upper limit and lower limit. The combination of the upper and lower limits of the addition rate may be, for example, 0.05 to 0.5 mol/hour and 0.1 to 0.5 mol/hour. However, the present invention is not limited at all by these combinations.

(Post-treatment; Isolation and/or Purification)

The compound of formula (B) as the object, in particular 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether ( B-a) is prepared by methods known to those skilled in the art (e.g., extraction, washing, crystallization including recrystallization, filtration, crystal washing and/or other manipulations) and improvements thereof, and any combination thereof, can be isolated and purified from

In the post-processing, crystallization of the target material including recrystallization and cleaning of the crystal may be performed. Crystallization of the object including recrystallization may be performed by conventional methods known to those skilled in the art. For example, a poor solvent may be added to a solution of a good solvent of the target substance. As another example, a saturated solution of the target substance may be cooled.

In any of the above cases, seed crystals may be used.

In the crystal washing operation, the crystals obtained by filtration may be washed with a solvent. After stirring the crystal suspension (slurry), you may filter it.

In addition, from the viewpoint of yield, purity and economic efficiency, etc., the filtration temperature is, for example, 0°C (zero°C) to 30°C, preferably 0°C (zero°C) to 20°C, more preferably 5°C. to 15°C.

In any of the above cases (crystallization operation including recrystallization, filtration operation, crystal washing tank, etc.), solvents such as organic solvents (including water-miscible organic solvents) and water are used. Examples of water-miscible organic solvents include, but are not limited to: nitriles (eg acetonitrile), alcohols (eg methanol, ethanol, 2-propanol, t-butanol), ethers. (e.g. tetrahydrofuran (THF), 1,4-dioxane), ketones (e.g. acetone), amides (e.g. N,N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.), and combinations thereof, preferably acetonitrile, methanol, ethanol, 2-propanol, t-butanol, acetone, and combinations thereof, more preferably Preferably acetonitrile, methanol, ethanol, 2-propanol, t-butanol and combinations thereof, more preferably 2-propanol or t-butanol.

The amount of the organic solvent such as a water-miscible organic solvent and the amount of water may be any ratio as long as the purpose is achieved. When using a combination of a water-miscible organic solvent and water, any ratio may be used as long as the purpose is achieved. When using a combination of two or more types of solvents such as water-miscible organic solvents, any ratio may be used as long as the purpose is achieved. Their amounts and ratios can be appropriately adjusted by those skilled in the art according to the purpose and circumstances.

In any of the above operations (extraction operation, washing operation, crystallization operation including recrystallization, filtration operation, crystal washing tank, etc.), the temperature can be appropriately adjusted by those skilled in the art. However, from the viewpoint of yield, purity, economic efficiency, etc., for example, the temperature is 0°C (zero°C) to 100°C, preferably 0°C to 50°C, more preferably 0°C to 35°C, still more preferably Preferably it is 5 ℃ to 35 ℃. Heating and cooling may be performed within these temperature ranges.

In any of the above operations (extraction operation, washing operation, crystallization operation including recrystallization, filtration operation, crystal washing tank, etc.), the amount of organic solvent (including water-miscible organic solvent) and/or water depends on their addition and removal. This can be appropriately adjusted by those skilled in the art. In addition, recovery and recycling of the solvent may be performed depending on the case. For example, the solvent used in the reaction may be recovered and recycled, or the solvent used in the post-treatment (isolation and/or purification) may be recovered and recycled.

Post-treatment (isolation and/or purification) can be performed by appropriately combining all or part of the above operations. If necessary, the above operation may be repeated according to the purpose of isolation and/or purification. In addition, a person skilled in the art can appropriately select a combination of any of the above operations and their order.

However, in the present invention, the target compound of formula (B), particularly 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl) ) Phenyl]ether (B-a) has a solubility of 30% to 40% in an alcohol solvent in the range of 15 to 20°C, so that crystals of the target product are precipitated at the end of the reaction. In this way, it is possible to simply purify the target object only by filtration. In this way, the target substance having a low melting point can be crystallized from the reaction mixture, and the compound of the formula (B) as the target substance having high purity can be efficiently produced industrially only by filtration.

(reaction yield and yield)

In this specification, the term "reaction yield" and the term "yield" have the following meanings, respectively.

(reaction yield)

In the present invention, the reaction yield was determined by analyzing the organic layer of the reaction mixture according to the following HPLC analysis conditions (A) or GC analysis conditions. In this specification, the reaction yield is expressed as HPLC area percentage of the target compound.

The reaction yield in the present invention may be, for example, in the range of 80 to 100%, preferably 85 to 100%, more preferably 90 to 100%, still more preferably 95 to 100%.

(transference number)

The yield in the present invention can be calculated from the number of moles of the obtained monosulfoxide compound (target compound) of the formula (B) relative to the number of moles of the sulfide derivative (raw material compound) of the formula (A). That is, the yield in the present invention is expressed by the following formula:

Yield (%) = (number of moles of target compound obtained) / (number of moles of raw material compound) × 100

The yield in the present invention may be, for example, in the range of 85 to 100%, preferably 90 to 100%.

Hereinafter, the present invention will be described in more detail by examples, but the present invention is not limited by these examples at all.

In this specification, the following equipment and conditions were used for measurement of each physical property and yield of Examples and Comparative Examples.

(GC: Gas Chromatography)

Device: GC-2030 (manufactured by Shimadzu Seisakusho Co., Ltd.)

Column: DB-17 (Agilent J&W)

Detection temperature: 280 ℃

Inlet temperature: 280°C

Total flow rate: 34 mL/min

Split ratio: 1:30

Injection volume: 1 μL

Oven temperature:

Regarding the GC analysis method, the following documents can be referred to as needed.

Japan Chemical Society Edition, "New Experimental Chemistry Lecture 9 Analytical Chemistry II", pp. 60-86 (1977), publisher Shingo Iizumi, Maruzen Co., Ltd.

Japan Chemical Society Edition, 「Experimental Chemistry Lecture 20-1 Analytical Chemistry」 5th Edition, pp. 121-129 (2007), publisher Seishiro Murata, Maruzen Co., Ltd.

(HPLC: High Performance Liquid Chromatography)

(HPLC analysis conditions)

Device: LC-20

Pump: LC-20AT (manufactured by Shimadzu Seisakusho Co., Ltd.)

Detector: SPD-20A (manufactured by Shimadzu Seisakusho Co., Ltd.)

Column: CERI L-column ODS (4.6 x 250 mm), L-C18, 5 μm, 12 nm

Eluent:

Flow Rate: 1.0 mL/min

Detection: UV 228 nm

Column temperature: 40°C

As described above, in the evaluation of the reaction yield, the area percentage under the above HPLC analysis conditions or GC analysis conditions was used.

Regarding the HPLC analysis method, the following literature can be referred to as needed.

Japan Chemical Society Edition, "New Experimental Chemistry Lecture 9 Analytical Chemistry II", pp. 86-112 (1977), publisher Shingo Iizumi, Maruzen Co., Ltd.

Japan Chemical Society Edition, “Experimental Chemistry Lecture 20-1 Analytical Chemistry” 5th Edition, pp. 130-151 (2007), publisher Seishiro Murata, Maruzen Co., Ltd.

（ ¹ H-NMR: ¹ H nuclear magnetic resonance spectrum; analysis condition)

Device: JEOL JMN-ECS-300 or JEOL JMN-Lambda-400 (manufactured by JEOL RESONANCE, Inc.)

Internal reference substance: tetramethylsilane (TMS)

(Melting point measurement method)

Measurements were made with DSC differential scanning calorimetry. Differential scanning calorimetry was performed at a heating rate of 10°C/min in a temperature range of 0 to 400°C using Model: DSC-60 (manufactured by Shimadzu Corporation). Regarding the differential scanning calorimetry method, the following documents can be referred to as needed. Journal of the Chemical Society of Japan, 「4th Edition, Column 4, Pressure in Experimental Chemistry」, pp. 57-93 (1992), Publishers Kumao Ebihara, Maruzen Co., Ltd.

The Chemical Society of Japan, 「Fifth Edition Experimental Chemistry Lecture 6 Temperature/Heat/Pressure」, pp. 203-205 (2005), publisher Seishiro Murata, Maruzen Co., Ltd.

In Examples and Comparative Examples of the present invention, a reaction vessel commonly used by those skilled in the art was used as a reaction vessel for preparation of the catalyst solution and preparation of the title compound. For example, in Comparative Example 11, a cross-shaped magnetic stirrer with an outer diameter (length) of 10 mm and a height (thickness) of 5 mm and a magnetic stirrer with a thermostat are provided. About 6 mL screw vial with an inner diameter of 15 mm and a height of 40 mm (vial with a screw cap) was used.

(Powder X-ray diffraction measurement)

Device: Rigaku MultiFlex

X-ray: Cu-Kα

Measurement method: reflection mode

Voltage: 40 kV

Current: 40 mA

Measurement range: 5 to 80°

Measuring interval: 0.02°

In this specification, room temperature is usually in the range of 10°C to 35°C.

In this specification, "age/aged/aging" includes stirring the mixture by a conventional method known to those skilled in the art.

Example 1

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 12]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (14.96 g, purity 87%, 30 mmol, 100 mol%), vanadyl acetylacetonate (79.5 mg, 0.3 mmol, 1 mol%) was added to 2-propanol (24 mL, 0.8 L/mol). The mixture was stirred at internal temperature 15-20° C. for 30 minutes. Thereto, 35% hydrogen peroxide (3.5 g, 36 mmol, 120 mol%) was added dropwise over 3 hours at an internal temperature of 15°C to 20°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 15°C to 20°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.5%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw material compound): 0.5%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9 %.

The reaction mixture was an orange-brown suspension at 15°C. Crystals of the target material were precipitated. To the reaction mixture was added 2.5% aqueous sodium sulfite solution (24.6 g, 6 mmol, 20 mol %), and the mixture was stirred at internal temperature at 5° C. for 1 hour. The obtained crude product was separated by filtration at 5°C. The obtained crystals were washed sequentially with a mixed solution of 12 mL (0.4 L/mol) of 2-propanol and 12 mL (0.4 L/mol) of water and 24 mL (0.8 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 90.5% (12.73 g, purity 95.2%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm, based on TMS): 1.57-1.66 (m, 2H), 1.74-1.93 (m, 4H), 2.92 (t, 2H), 3.30-3.43 (m, 1H) ), 3.66-3.78 (m, 1H), 4.13 (t, 2H), 7.21 (d, 1H), 7.54 (d, 1H)

Melting Point: 43℃

This was an industrially excellent production method in which a target substance having a low melting point could be crystallized from the reaction mixture and a high-purity product could be obtained only by filtration.

Example 2

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 13]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (9.78 g, purity 88%, 20 mmol, 100 mol%), vanadyl acetylacetonate (53 mg, 0.2 mmol, 1 mol%) was added to 2-propanol (20 mL, 1.0 L/mol). The mixture was stirred at internal temperature 15-20° C. for 30 minutes. Thereto, 33% hydrogen peroxide (3.09 g, 30 mmol, 150 mol%) was added dropwise over 3 hours at an internal temperature of 15°C to 20°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 15°C to 20°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.0%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw material compound): 0.2%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9 %.

The reaction mixture was an orange-brown suspension at 15°C. Crystals of the target material were precipitated. To the reaction mixture was added 13.3% sodium sulfite aqueous solution (8.5 g, 10 mmol, 0.5 mol%), and the mixture was stirred at internal temperature 5°C for 1 hour. The obtained crude product was separated by filtration at 5°C. The obtained crystals were washed sequentially with a mixed solution of 5 mL (0.4 L/mol) of 2-propanol and 9 mL (0.4 L/mol) of water, and 20 mL (0.8 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 94.5% (8.73 g, purity 96.7%).

Example 3

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 14]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (9.78 g, purity 88%, 20 mmol, 100 mol%), vanadyl acetylacetonate (53 mg, 0.2 mmol, 1 mol%) was added to 2-propanol (10 mL, 0.5 L/mol). The mixture was stirred at internal temperature 15-20° C. for 30 minutes. Thereto, 33% hydrogen peroxide (3.09 g, 30 mmol, 150 mol%) was added dropwise over 3 hours at an internal temperature of 15°C to 20°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 15°C to 20°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 91.4%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 3.5%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.5 %.

Example 4

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 15]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (9.78 g, purity 88%, 20 mmol, 100 mol%), vanadyl acetylacetonate (53 mg, 0.2 mmol, 1 mol%) was added to 2-propanol (20 mL, 1.0 L/mol). The mixture was cooled to an internal temperature of 5° C. and stirred for 30 minutes. 33% hydrogen peroxide (3.09 g, 30 mmol, 150 mol%) was added there dropwise over 3 hours at an internal temperature of 5°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 5°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 93.2%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 1.9%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.5 %.

Example 5

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 16]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), vanadyl acetylacetonate (26.5 mg, 0.1 mmol, 2 mol%) was added to methanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.8%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.6%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.9 %.

Example 6

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 17]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), vanadium(III) acetylacetonate (34.8 mg, 0.1 mmol, 2 mol%) was added to methanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.5%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 0.8%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4 %.

Example 7

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 18]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), vanadium(III) acetylacetonate (34.8 mg, 0.1 mmol, 2 mol%) was added to acetonitrile (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 85.6%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 8.4%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.3 %.

Example 8

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 19]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.29 g, purity 93 %, 5 mmol, 100 mol%), titanyl(IV) acetylacetonate (26.2 mg, 0.1 mmol, 2 mol%) was added to methanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 63 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 87.2%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 2.0%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 5.2 %.

Example 9

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 20]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), ammonium molybdate tetrahydrate (8.7 mg, 0.007 mmol, 0.14 mol%, 1 mol% as molybdenum atoms) was added to 2-propanol (4 mL, 0.8 L/mol). . The mixture was cooled to an internal temperature of 0°C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at an internal temperature of 0° C. for 30 minutes and then aged at room temperature for 17 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.6%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw material compound): 0.5%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.2 %.

The reaction mixture was a yellow suspension at 25°C. Crystals of the target material were precipitated.

Example 10

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 21]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.15 g, purity 94 %, 5 mmol, 100 mol%), ammonium molybutate tetrahydrate (8.7 mg, 0.007 mmol, 0.14 mol%, 1 mol% as molybdenum atoms) was added in acetonitrile (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 87.6%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.3%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 7.0 %.

Example 11

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 22]

In a 250 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (33.1 g, purity 88%, 80 mmol, 100 mol%), vanadyl acetylacetonate (212.1 mg, 0.8 mmol, 1 mol%) was added to t-butanol (60 mL, 0.8 L/mol). The mixture was stirred at internal temperature 25° C. for 30 minutes. 35% hydrogen peroxide (9.3 g, 96 mmol, 120 mol%) was added there dropwise over 3 hours at an internal temperature of 25°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 25°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 96.1%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw material compound): 0.2%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4 %.

The reaction mixture was an orange-brown solution at 25°C. To the reaction mixture were added t-butanol (8 mL, 0.1 L/mol) and 2% aqueous sodium bisulfite solution (40.8 g, 8 mmol, 10 mol%), and the mixture was stirred at an internal temperature of 20° C. for 1 hour. The obtained crude product was separated by filtration at 20°C. The obtained crystals were washed sequentially with a mixed solution of 20 mL (0.3 L/mol) of 2-propanol and 36 mL (0.5 L/mol) of water and 24 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 85.1% (31.5 g, purity 96.6%).

Example 12

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 23]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%), vanadyl acetylacetonate (66.3 mg, 0.25 mmol, 1 mol%) was added to t-butanol (19 mL, 0.8 L/mol). The mixture was stirred at internal temperature 40° C. for 30 minutes. Thereto, 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added dropwise over 3 hours at an internal temperature of 40°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 40°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.6%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.7%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4 %.

A 9.4% aqueous sodium hydrogensulfite solution (2.8 g, 2.5 mmol, 10 mol%) and 10 mL (0.4 L/mol) of water were added to the reaction mixture, and the mixture was stirred at an internal temperature of 20° C. for 1 hour. The obtained crude product was filtered at 20°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L/mol) of 2-propanol and 11 mL (0.5 L/mol) of water and 8 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 86.2% (9.9 g, purity 96.9%).

Example 13

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 24]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%), vanadyl acetylacetonate (66.3 mg, 0.25 mmol, 1 mol%) was added to t-butanol (19 mL, 0.8 L/mol). The mixture was stirred at internal temperature 30 °C for 30 minutes. 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added there dropwise over 3 hours at an internal temperature of 30°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 30°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.1%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.9 %.

To the reaction mixture was added 2% aqueous sodium hydrogen sulfite solution (12.8 g, 2.5 mmol, 10 mol%), and the mixture was stirred at an internal temperature of 15° C. for 1 hour. The obtained crude product was filtered off at 15°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L/mol) of 2-propanol and 11 mL (0.5 L/mol) of water and 8 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 84.4% (9.69 g, purity 97.3%).

Example 14

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 25]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%), vanadyl acetylacetonate (33.2 mg, 0.13 mmol, 0.5 mol%) was added to t-butanol (19 mL, 0.8 L/mol). The mixture was stirred at internal temperature 30 °C for 30 minutes. 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added there dropwise over 3 hours at an internal temperature of 30°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 30°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 96.6%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.6%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4 %.

To the reaction mixture was added 2% sodium hydrogen sulfite aqueous solution (12.8 g, 2.5 mmol, 10 mol %), and the mixture was stirred at an internal temperature of 15° C. for 1 hour. The obtained crude product was filtered off at 15°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L/mol) of 2-propanol and 11 mL (0.5 L/mol) of water and 8 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 87.3% (9.84 g, purity 99.1%).

Example 15

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 26]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%), vanadyl acetylacetonate (66.4 mg, 0.25 mmol, 1 mol%) was added to t-butanol (13 mL, 0.5 L/mol). The mixture was stirred at internal temperature 30 °C for 30 minutes. Thereto, 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added dropwise over 3 hours at an internal temperature of 30°C, and the mixture was aged for 2 hours while maintaining the internal temperature at 30°C. Further, 35% hydrogen peroxide (0.24 g, 2.5 mmol, 10 mol%) was added at an internal temperature of 30°C, and the mixture was aged for 30 minutes while maintaining the internal temperature at 30°C.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.6%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.6%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.3 %.

Example 16

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 27]

In a 250 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (44.0 g, purity 88%, 90 mmol, 100 mol%), vanadyl acetylacetonate (239 mg, 0.9 mmol, 1 mol%) in t-butanol (77 mL, 0.9 L/mol), water (6 mL, 0.1 L/mol) ) was added. The mixture was stirred at internal temperature 30 °C for 30 minutes. Thereto, 34% hydrogen peroxide (11 g, 108 mmol, 120 mol%) was added dropwise over 3 hours at an internal temperature of 30°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 30°C.

The reaction mixture was analyzed by GC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 96.8%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw material compound): 0.5%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9 %.

The reaction mixture was an orange-brown solution at 30°C. To the reaction mixture was added 9.4% sodium hydrogen sulfite aqueous solution (9.9 g, 9.0 mmol, 10 mol%), and the mixture was stirred at internal temperature of 20° C. for 30 minutes. Seed crystals were added to the mixture at an internal temperature of 20°C, the mixture was cooled to an internal temperature of 5°C over 1 hour, and aged for 14 hours. The obtained crude product was separated by filtration at 5°C. The obtained crystals were washed sequentially with a mixed solution of 23 mL (0.3 L/mol) of t-butanol and 41 mL (0.5 L/mol) of water and 27 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 88.9% (37.1 g, purity 96.6%).

As seed crystals used in the above examples, crystals obtained in the same manner as in Example 1 were used.

Example 17

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 28]

In a 250 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (38.9 g, purity 89%, 80 mmol, 100 mol%), vanadyl acetylacetonate (212 mg, 0.8 mmol, 1 mol%) in t-butanol (68 mL, 0.9 L/mol), water (5 mL, 0.1 L/mol) ) was added. The mixture was stirred at internal temperature 30 °C for 30 minutes. 35% hydrogen peroxide (9.3 g, 96 mmol, 120 mol%) was added there dropwise over 3 hours at an internal temperature of 30°C, and the mixture was aged for 1 hour while maintaining the internal temperature at 30°C.

The reaction mixture was analyzed by GC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 97.1%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.6%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4 %.

The reaction mixture was an orange-brown solution at 30°C. To the reaction mixture was added 3.7% aqueous sodium bisulfite solution (22.7 g, 8 mmol, 10 mol%), and the mixture was cooled from internal temperature 30°C to 25°C over 30 minutes. Seed crystals were added to the mixture at an internal temperature of 25°C, the mixture was cooled to an internal temperature of 5°C over 1 hour, and aged for 2 hours. The obtained crude product was separated by filtration at 5°C. The obtained crystals were washed sequentially with a mixed solution of 20 mL (0.3 L/mol) of t-butanol and 36 mL (0.5 L/mol) of water and 24 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 91.5% (33.6 g, purity 97.4%).

As seed crystals used in the above examples, crystals obtained in the same manner as in Example 1 were used.

Example 18

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 29]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.1 g, purity 88%, 25 mmol, 100 mol%), vanadyl acetylacetonate (66.4 mg, 0.25 mmol, 1 mol%) was added to t-butanol (19 mL, 0.8 L/mol). The mixture was stirred at internal temperature 30 °C for 30 minutes. 35% hydrogen peroxide (1.0 g, 10 mmol, 40 mol%) was added dropwise over 1 hour at an internal temperature of 30°C, and then 35% hydrogen peroxide (2.0 g, 20 mmol, 80 mol%) was added dropwise at an internal temperature of 20°C. It was added dropwise over 2 hours while cooling, and the mixture was aged for 1 hour while maintaining the internal temperature at 20°C.

The reaction mixture was analyzed by GC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 97.6%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.6%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9 %.

The reaction mixture was an orange-brown suspension at 20°C. Crystals of the target material were precipitated. To the reaction mixture was added 5% aqueous sodium bisulfite solution (5.3 g, 2.5 mmol, 10 mol%) and 5 mL of water (0.2 L/mol). The mixture was stirred at internal temperature 15° C. for 1 hour. The obtained crystals were separated by filtration at 15°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L/mol) of 2-propanol and 11 mL (0.5 L/mol) of water and 8 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 86.2% (9.9 g, purity 97.7%).

Example 19

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 30]

In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.1 g, purity 88%, 25 mmol, 100 mol%), vanadyl acetylacetonate (66.4 mg, 0.25 mmol, 1 mol%) was added to t-amyl alcohol (19 mL, 0.8 L/mol). The mixture was stirred at internal temperature 17° C. for 30 minutes. 33.7% hydrogen peroxide (3.0 g, 30 mmol, 120 mol%) was added there dropwise over 3 hours at an internal temperature of 17°C, and aged for 1 hour.

The reaction mixture was analyzed by GC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 97.4%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 0.7%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.5 %.

The reaction mixture was an orange-brown suspension at 17°C. A 5% aqueous solution of sodium hydrogensulfite (5.3 g, 2.5 mmol, 10 mol%) and 15 mL (0.6 L/mol) of water were added to the reaction mixture, and the mixture was stirred at an internal temperature of 40°C for 5 minutes. The resulting mixture was separated into an organic layer and an aqueous layer. Then, the obtained organic layer was concentrated under reduced pressure, and the solvent was distilled off. 2-propanol (19 mL, 0.8 L/mol) and water (5 mL, 0.2 L/mol) were added to the crude product, and the mixture was heated to an internal temperature of 40°C. The internal temperature was cooled to 10° C. over 2 hours and aged for 1 hour. The obtained crystals were separated by filtration at 10°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L/mol) of 2-propanol and 11 mL (0.5 L/mol) of water and 8 mL (0.3 L/mol) of water. As a result, white crystals of the target product (Compound B-a) were obtained in a yield of 85.9% (9.9 g, purity 96.6%).

NMR data of disulfoxide derivatives, which are by-products, are described.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm, based on TMS): 1.67-1.79 (m, 2H), 1.90-2.01 (m, 4H), 2.86-2.96 (m, 1H), 3.08-3.17 (m , 1H), 3.33-3.41(m, 1H), 3.68-3.76(m, 1H), 4.15(t, 2H), 7.23(d, 1H), 7.55(d, 1H)

A compound in which a sulfide adjacent to R ¹ is oxidized was not identified in the above examples.

Comparative Example 1

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 31]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.60 g, purity 82.7 %, 5 mmol, 100 mol%), manganese(III) acetylacetate (35 mg, 0.1 mmol, 2 mol%) was added to methanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 93.6%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 2

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 32]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.30 g, purity 93.9 %, 5 mmol, 100 mol%), iron(III) acetylacetate (17.7 mg, 0.05 mmol, 1 mol%) was added to methanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 93.6%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 3

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 33]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), zirconium(IV) oxychloride octahydrate (32 mg, 0.1 mmol, 2 mol%) was added in methanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 20 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 2.1%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 93.4%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 4

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 34]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), sodium tungstate dihydrate (29.3 mg, 0.1 mmol, 2 mol%) was added to 2-propanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 20 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 23.4%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 72.2%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.1 %.

Comparative Example 5

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 35]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), ammonium paratungstate pentahydrate (13.1 mg, 0.004 mmol, 0.08 mol%, 1 mol% as tungsten atom) was added in methanol (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 20 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 7.3%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 88.3%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 6

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 36]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.60 g, purity 82.7 %, 5 mmol, 100 mol%), manganese(III) acetylacetate (35 mg, 0.1 mmol, 2 mol%) was added to acetonitrile (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 93.3%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 7

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 37]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.30 g, purity 93.9 %, 5 mmol, 100 mol%), iron(III) acetylacetate (17.7 mg, 0.05 mmol, 1 mol%) was added to acetonitrile (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0.9%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 93.8%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 8

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 38]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), zirconium(IV) oxychloride octahydrate (32 mg, 0.1 mmol, 2 mol%) was added to acetonitrile (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 20 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 1%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 94.4%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 9

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 39]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (4.7 g, purity 90.4 %, 10 mmol, 100 mol%), sodium tungstate dihydrate (164 mg, 0.5 mmol, 5 mol%) was added to acetonitrile (5 mL, 0.5 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (1.2 g, 12 mmol, 120 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 69 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 26%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 65.8%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 10

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Reconciliation 40]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87 %, 5 mmol, 100 mol%), ammonium paratungstate pentahydrate (13.1 mg, 0.004 mmol, 0.08 mol%, 1 mol% as tungsten atom) was added in acetonitrile (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 20 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 1.5%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw compound): 94.1%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 11

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 41]

(1) Preparation of catalyst solution

In a screw-capped vial, vanadyl acetylacetonate (1.3 mg, 0.005 mmol, 1 mol%), (E)-2-{[(1-hydroxy-2-methylpropan-2-yl)imino]methyl } Phenol (ligand of (3-4) described in WO2017/150478 (Patent Document 2), 1.0 mg, 0.005 mmol, 1 mol%), sodium 2,6-dimethoxybenzoate (WO2017/150478 (Patent Document 2) A benzoic acid derivative of (4-1) described, 5.1 mg, 0.025 mmol, 5 mol%) and dichloromethane (1 mL, 0.5 L/mol) were added. The mixture was stirred at room temperature for 30 minutes.

(2) Preparation of the title compound

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (244 mg, purity 88.2%, 0.500 mmol, 100 mol %) was dissolved in dichloromethane (1 mL, 0.5 L/mol). The catalyst solution prepared in (1) above was added there. The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (97.1 mg, 1.0 mmol, 200 mol%). The mixture was stirred at 0 °C for 15 hours. The organic layer of the reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 1.2%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 92.3%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 11 was carried out by changing the metal catalyst of WO2017/150478 (Patent Document 2) from an iron catalyst to a vanadium catalyst. It was difficult to obtain the target object (B) of the present invention only by changing the metal catalyst.

by-products;

Comparative Example 12

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 42]

In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.30 g, purity 93.9 %, 5 mmol, 100 mol%), iron(III) acetylacetate (17.7 mg, 0.05 mmol, 1 mol%) was added to dichloromethane (4 mL, 0.8 L/mol). The mixture was cooled to 0 °C. Thereto was added 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol %). The mixture was stirred at 0° C. for 30 minutes and then aged at room temperature for 24 hours.

The reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 2.3%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 93.2%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 13

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 43]

To a 250 mL reaction flask was added 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (14.65 g, purity 88). %, 30 mmol, 100 mol%), vanadyl acetylacetonate (318 mg, 1.2 mmol, 4 mol%) and chloroform (40 mL, 1.3 L/mol) were added, and the mixture was stirred at an internal temperature of 25° C. for 10 minutes. Then, 35% hydrogen peroxide (5.24 g, 54 mmol, 180 mol%) was added dropwise to the mixture over 10 minutes. After aging for 4 hours at an internal temperature of 25° C., the organic layer of the reaction mixture was analyzed by HPLC (area percentage). As a result, components other than the solvent and the like in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 2.2%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 93.7%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Comparative Example 14

Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[Formula 44]

To a 250 mL reaction flask was added 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (14.65 g, purity 88). %, 30 mmol, 100 mol%), vanadyl acetylacetonate (318 mg, 1.2 mmol, 4 mol%) and chloroform (40 mL, 1.3 L/mol) were added, and the mixture was stirred at an internal temperature of 25° C. for 10 minutes. Then, (S)-(2,4-di-tert-butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutan-2-yl)imino]methyl}phenol ( 600 mg, 1.8 mmol, 6 mol%) was added. After 10 minutes, 35% hydrogen peroxide (5.24 g, 54 mmol, 180 mol%) was added dropwise over 10 minutes. , The organic layer of the reaction mixture was analyzed by HPLC (area percentage) As a result, components other than the solvent etc. in the reaction mixture were as follows;

5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 17.5%,

5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl] ether (raw compound): 70.5%,

5-Trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0 %.

Aging was continued for 20 hours, but the reaction did not change from that at 4 hours.

Comparative Example 13 and Comparative Example 14 were the follow-up of the prior art using a ligand and a vanadium catalyst. In Comparative Example 13, in the method of US2011/0015405A1 (Japanese Patent Publication No. 2012-532906) (Patent Document 3) and Example 1, the reaction was performed without using a ligand as in Examples of the present invention. It was difficult to obtain the target product (B) of this reaction only by changing whether the ligand was used or not. In Comparative Example 14, the same reaction was performed using the same metal catalyst, ligand, oxidizing agent, and solvent as in US2011/0015405A1 (Japanese Patent Application No. 2012-532906) (Patent Document 3) and Example 1. As shown in Comparative Example 14, even if the method of the prior art was applied to the raw material of the present invention, the reaction did not proceed sufficiently. It has been confirmed that the prior art cannot be applied to the preparation of the subject matter of the present invention.

Example 20

In the same production method as in Example 16, white crystals of the compound of formula (B-a) were obtained. Here, crystals obtained in the same manner as in Example 16 were used as seed crystals. The obtained crystals were vacuum dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction analysis. The powder X-ray diffraction measurement results are shown in FIG. 1 .

Example 21

In the same production method as in Example 16, white crystals of the compound of formula (B-a) were obtained. Here, crystals obtained in the same manner as in Example 16 were used as seed crystals. The resulting crystals were melted and dried under reduced pressure to remove moisture, and then cooled. The obtained crystals were pulverized with a mill. The melting point was 47°C to 48°C. The obtained crystals were subjected to powder X-ray diffraction analysis. The powder X-ray diffraction measurement results are shown in FIG. 2 .

Example 22

In the same production method as in Example 1, white crystals of the compound of formula (B-a) were obtained. Recrystallization was performed on the obtained crystal. Here, the recrystallization conditions were the same as those of Example 1 (recrystallization from 2-propanol and water). The obtained crystals were filtered and dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction analysis. The powder X-ray diffraction measurement results are shown in FIG. 3 .

Reference Manufacturing Example 1

Preparation of 4-fluoro2-chlorophenol

[Formula 45]

In a 1000 mL reaction flask, 2-fluorophenol (112.1 g, 100% purity, 1000 mmol, 100 mol%), diphenylsulfide (372.5 mg, 2.000 mmol, 0.2 mol%), anhydrous iron(III) chloride (162.2 mg, 1.000 mmol, 0.1 mol%) was added to dichloromethane (610 mL, 0.61 L/mol). The mixture was stirred at internal temperature 5-10 °C for 30 minutes. Chlorine gas (70.9 g, 1000 mmol, 100 mol%) was blown therein at an internal temperature of 5°C to 10°C over 6 hours, and the mixture was aged for 1 hour while maintaining the internal temperature at 5°C to 10°C.

The reaction mixture was a yellow clear liquid at 10 °C. Nitrogen gas was blown into the reaction mixture at 60 mL/min for 2 hours. As a result, a dichloromethane solution of the target material was obtained in a yield of 97% (909.7 g, purity 15.6%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm, based on TMS): 5.09 (d, 1H), 6.94 (dd, 1H), 7.02 (ddd, 1H), 7.11 (dd, 1H)

As disclosed in Patent Document 1, the monosulfoxide derivative of formula (B) has excellent acaricidal activity.

According to the present invention, there is provided a novel, industrially preferable method for producing monosulfoxide derivatives of the formula (B) useful as pesticides such as acaricides.

As described above in this specification, the method of the present invention is economical, environmentally friendly, and has high industrial utility value.

In particular, in the method of the present invention, excessive oxidation to a disulfoxide derivative can be avoided, and a target monosulfoxide derivative can be selectively produced. In addition, a simple operation without using a ligand is possible.

Therefore, the present invention has an advantage that it is not necessary to remove the disulfoxide derivative, which is a by-product that is difficult to remove.

In short, the present invention has high industrial applicability.

All publications, patents and patent applications described herein are hereby incorporated by reference for the purpose of describing and disclosing the methods described in those publications, patents and patent applications that may be used in conjunction with the description herein. is fully incorporated into it. To the extent necessary to understand or complete the disclosure of this invention, all publications, patents and patent applications described herein are expressly incorporated herein by reference to the same extent as if each were individually incorporated. All publications, patents and patent applications discussed above and throughout this specification are provided solely for disclosure prior to the filing date of the present application.

Any methods and reagents identical or equivalent to those described herein can be used in the methods and practice of the present invention. Accordingly, the present invention is not intended to be limited by the foregoing description, but is intended to be defined by the claims and equivalents thereof. Their equivalents fall within the scope of this invention as defined by the appended claims.

Claims (16)

As a method for preparing the compound of formula (B),
A method comprising an oxidation process wherein a compound of formula (A) is reacted with hydrogen peroxide in the presence of a metal catalyst:

(In the expression,
R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;
R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 halo an alkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; and
n is 5 or 6.)

(In the formula, R ¹ , R ² , R ³ and n are as defined above.) The method of claim 1,
A method in which the metal catalyst is at least one catalyst selected from the group consisting of vanadium catalysts, molybdenum catalysts and titanium catalysts. The method of claim 1,
A method in which the metal catalyst is a vanadium catalyst. The method according to any one of claims 1 to 3,
A method in which the oxidation process is carried out in a solvent. The method of claim 4,
A method in which the solvent is a solvent in which the solubility of the compound of formula (A) is high and the solubility of the compound of formula (B) is low. According to claim 4 or claim 5,
A method in which the solvent is a solvent comprising an alcohol. The method of claim 6,
The method in which the alcohol is a C1-C6 fatty alcohol. According to claim 6 or claim 7,
A process in which the alcohol is methanol, ethanol, 2-propanol, t-butanol or t-amyl alcohol. According to claim 6 or claim 7,
A method in which the alcohol is methanol, 2-propanol, t-butanol or t-amyl alcohol. The method according to any one of claims 4 to 6,
A method in which the solvent is a nitrile solvent or an alcohol solvent, or a mixture of a nitrile solvent or alcohol solvent and water. The method according to any one of claims 4 to 6,
A process in which the solvent is acetonitrile, methanol, 2-propanol, t-butanol or t-amyl alcohol, or a mixture thereof with water. According to any one of claims 1 to 11,
A method comprising a step of recovering crystals of the compound of formula (B) after the oxidation step. According to any one of claims 1 to 12,
The method in which the content of the compound of formula (C) is 10% or less by weight of the compound of formula (B):

(In the expression,
R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;
R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalky a nyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also
n is 5 or 6.) The method according to any one of claims 1 to 13,
A method in which the compound of formula (B) is a crystal. As a compound of formula (B),
A compound of formula (B) wherein the content of the compound of formula (C) is 10% or less by weight of the compound of formula (B):

(In the expression,
R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;
R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalky a nyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; and
n is 5 or 6)

(In the expression,
R ¹ is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group or a C2-C4 haloalkynyl group;
R ² and R ³ are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalky a nyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; and
n is 5 or 6.) The powder X-ray diffraction spectrum shows diffraction angles 2θ = 8.9°±0.2°, 10.3°±0.2°, 13.6°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 20.5°±0.2°, 21.9°±0.2°. Equation (Ba ) Determination of the compound of:

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